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Guidance for the Clinician in Rendering Pediatric Care Clinical Report—Health Supervision for Children With Fragile X Syndrome

Joseph H. Hersh, MD, Robert A. Saul, MD, and COMMITTEE abstract ON GENETICS Fragile X syndrome (an FMR1–related disorder) is the most commonly KEY WORDS fragile X syndrome, FMR1–related conditions, mental inherited form of mental retardation. Early physical recognition is dif- retardation, health guidelines ficult, so boys with developmental delay should be strongly considered ABBREVIATIONS for molecular testing. The characteristic adult phenotype usually does FMR1—fragile X mental retardation 1 not develop until the second decade of life. Girls can also be affected CGG—cytosine-guanine-guanine FMRP—fragile X mental retardation 1 with developmental delay. Because multiple family members can be mGluR—metabotropic glutamate receptor affected with mental retardation and other conditions (premature POI—primary ovarian insufficiency ovarian failure and /), family history information is of FXTAS—fragile X–associated tremor/ataxia syndrome critical importance for the diagnosis and management of affected pa- This document is copyrighted and is property of the American tients and their families. This report summarizes issues for fragile X Academy of and its Board of Directors. All authors have filed conflict of interest statements with the American syndrome regarding clinical diagnosis, laboratory diagnosis, genetic Academy of Pediatrics. Any conflicts have been resolved through counseling, related health problems, behavior management, and age- a process approved by the Board of Directors. The American related health supervision guidelines. The diagnosis of fragile X syn- Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of drome not only involves the affected children but also potentially has this publication. significant health consequences for multiple generations in each fam- The guidance in this report does not indicate an exclusive ily. Pediatrics 2011;127:994–1006 course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be INTRODUCTION appropriate. This set of guidelines was designed to assist pediatricians in caring for children with fragile X syndrome after a diagnosis has been confirmed by DNA analysis. Fragile X syndrome (secondary to an abnormality in the fragile X mental retardation 1 [FMR1] gene) is the most commonly inherited form of mental retardation. The disorder affects the child and potentially the mother and other family members. These guidelines, therefore, discuss issues pertinent to the clinical manifestations of this disorder in younger and older people. The multiple manifestations in different age groups have led to fragile X syndrome being designated www.pediatrics.org/cgi/doi/10.1542/peds.2010-3500 as one in the spectrum of FMR1-related disorders.1 doi:10.1542/peds.2010-3500 Awareness that mental retardation has a sex-linked component, with All clinical reports from the American Academy of Pediatrics 2 an excess of males affected, has existed for more than a century. This automatically expire 5 years after publication unless reaffirmed, observation led to the suggestion that affecting cognition were revised, or retired at or before that time. located on the X . In 1943, Martin and Bell3 reported that PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). mental retardation segregated as an X-linked gene in a family in which Copyright © 2011 by the American Academy of Pediatrics both males and were affected. Twenty-six years later, in 1969, Lubs4 reported a distinctive fragile site on the , which required 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. In 1977, the relationship of this fragile site at band q27.3 on the long arm of the X chromosome (Xq27.3) to X-linked mental retardation was con- firmed, and fragile X syndrome, as a clinical entity, was defined. Since

994 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS that time, the clinical and molecular is the degree of FMR1 and drome; mean age at diagnosis is 32 features of the condition have been gene-silencing rather than the length months. The classical facial appear- more clearly delineated. Several liter- of expansion reflected by the number ance that includes a prominent fore- ature sources are available for addi- of CGG repeats, which explains why 2 head, a long, narrow face, a prominent tional information.1,5–7 New informa- people with the same number of ex- jaw, and protuberant ears becomes tion regarding the role of the protein panded CGG repeats but different more evident late in childhood or in product in synaptic plasticity in the FMRP levels will have different clinical early adolescence. The palate fre- brain is under investigation.8 presentations, because methylation quently is highly arched, and cleft pal- The clinical phenotype of fragile X syn- may differ. Classically, in a person with ate has been reported. Dental crowd- drome, including cognitive abilities, is a full , the repeat number is ing and malocclusion are common. variable, and physical features often massively expanded. Premutations, may be present, and re- are nonspecific in nature, especially in which have a CGG repeat number that fractive errors, including hyperopia young children. The disorder has been ranges from 55 to 200, are meiotically and astigmatism, are present in 23% described in every ethnic group and unstable in the . Premutations to 50% of cases. Nystagmus and ptosis has an estimated prevalence of 1 in are unmethylated, are transcription- also are occasional ocular findings. 3700 white males and 1 in 2500 black ally active, and produce FMRP, al- Macro-orchidism is observed in more though possibly in lower amounts than males.1 Clinical manifestations of frag- than 80% of adolescent and adult normal . Repeats in the range of ile X syndrome also may occur in males with fragile X syndrome; mean 45 to 54 are considered to be interme- heterozygous females, in whom the testicular volume is approximately 50 diate or “gray-zone” alleles and are not prevalence is estimated to be 1 in 7000. mL (normal mean testicular volume: considered to be predisposed to mei- Ͻ25 mL). Macro-orchidism is less otic instability.1 Molecular clinical Molecular Basis of Fragile X common in prepubertal boys. Fragile X correlations have demonstrated that Syndrome syndrome also has a connective tissue variation in the clinical phenotype of dysplasia, and findings may include Cytogenetic assay for fragile X syn- affected people is related to the soft velvet-like skin; joint hypermobil- drome is no longer regarded to be suf- presence of mosaicism of methyl- ity, especially in the fingers; pes pla- ficiently precise for clinical diagnostic ation status, which results in preser- nus; congenital hip dislocation; scolio- use. In 1991, the FMR1 gene was vation of some gene function and 5,9 sis and clubfoot; and, in adults, mapped to the fragile site at Xq27.3. partial expression of FMRP. Although occasionally mitral valve prolapse.6 FMR1 harbors a novel, unstable CGG most instances of fragile X syndrome (cytosine-guanine-guanine) trinucle- result from CGG expansion into the Feeding problems are common, and otide repeat within the 5=-untranslated full mutation range, a rare point mu- gastroesophageal reflux has been re- region of the gene, which accounts tation within the FMR1 gene or dele- ported for one-third of affected in- both for the fragile site and the genetic tion in FMR1 can produce the typical fants. Chronic , seen in peculiarities associated with the re- phenotype of fragile X syndrome as 60% to 80% of cases, has its onset gion. The CGG repeat is highly polymor- well. early in life, and recurrent otitis me- phic in the general population. The nor- dia is present in 23% of males with mal range is from 5 to 40, and 30 CGG Clinical Phenotype fragile X syndrome. have repeats represents the most common The clinical phenotype in males with been reported in approximately 13% number found within the gene. Full mu- fragile X syndrome can be subtle, and to 18% of affected males and 5% of tations, which cause fragile X syn- its detection in the prepubertal period females with a full mutation, and drome, are the consequence of unsta- can be difficult. In fact, it was reported there may be relative . ble expansion of the repeats, which from a parent survey that 24% of fam- Birth weight in affected people typi- results in a CGG number that exceeds ilies with a child in whom fragile X syn- cally is normal. Accelerated linear 200. A full mutation results in hyper- drome was diagnosed had seen a growth with tall stature is common methylation of FMR1, which leads to health care provider more than 10 throughout childhood; however, gene-silencing and a decrease in the times before fragile X testing was per- growth velocity tends to slow in ado- production of the fragile X mental re- formed.10 Often, it is the presence of lescence, and 26% of adult men with tardation 1 protein (FMRP). The most development delay, mental retarda- fragile X syndrome have a height that important factor that determines the tion, or specific behavioral patterns is equal to or less than the 5th clinical severity of fragile X syndrome that leads to suspicion of fragile X syn- percentile.6(p27–28)

PEDIATRICS Volume 127, Number 5, May 2011 995 A subgroup of males with the full Neurobiology Hypersensitivity to sensory stimuli can mutation has been described in which Gross abnormalities have not been ob- lead to heightened and prolonged the clinical phenotype is reminiscent of served in the brains of people with arousal in situations in which there is 11 Prader-Willi syndrome. Affected fragile X syndrome on autopsy. Al- excessive auditory, visual, or tactile males have extreme obesity, short though diffuse brain atrophy and white stimuli. This behavior can lead to an stature, stubby hands and feet, and matter abnormalities have been noted increase in tantrums, hyperactivity, diffuse hyperpigmentation. on MRI, routine neuroimaging of the oppositionality, and restricted verbal brain is not indicated. At the cellular output. On the other hand, affected Cognitive Profile level, longer and thinner dendritic males often have a good sense of hu- Fragile X syndrome should be sus- spines on which most of the mor, are persistent and hardworking, pected in a boy with developmental de- occur have been detected, which sug- and have an endearing quality. Fea- tures of may be present in early lay and in early childhood. gests a possible misregulation in their childhood, including such Cognitive deficits frequently result in development and maturation. FMRP as hand-flapping, biting, perseverative moderate-to-severe mental retarda- has an important role in the regulation speech, poor eye contact, and lack of tion; the average IQ is approximately 40 of protein synthesis at a local level in interest in social interaction. Autism is in an adult man with a completely the of . Protein syn- present in 30% of people with a full methylated full mutation. Males who thesis in dendritic spines is important mutation, and pervasive developmen- are less severely affected can have in- for synaptic transmission, synaptic tal disorder–not otherwise specified complete methylation resulting in plasticity, learning, and memory. A pro- has been reported in another 20% to some gene product and present with posed role for FMRP at the is 30% of affected children. Fragile X syn- only mild intellectual deficits or learn- that it is a negative regulator of protein drome also is found in approximately ing problems. In addition, slowing in synthesis stimulated by group 1 metabo- 2% to 6% of people with autism. Psychi- the acquisition of cognitive skills can tropic glutamate receptor (mGluR) acti- atric comorbidity also is frequently ob- occur with age. vation.8 Therefore, fragile X syndrome served in affected people and includes is at least partially a result of exagger- Language delay also is evident in early oppositional defiant disorder, separa- ated responses to mGluR stimulation. childhood. A child with fragile X syn- tion anxiety, and obsessive-compulsive drome may not begin to speak until 2 to 3 disorder. Females with a full muta- Behavioral Phenotype years of age. Although vocabulary and tion tend to have a higher risk of syntax may be less involved, deficits in Behavioral problems occur in more emotional problems compared with conversational speech are frequent. than 50% of affected patients and are the general population. In fact, shy- In females with a full mutation, the cog- generally out of proportion with the af- ness, social avoidance, social anxi- nitive profile is similar to that of males, fected child’s cognitive level, compared ety, mood lability, and depression but there is wider phenotypic variabil- with children with other developmental may be presenting features in a fe- ity, especially in relation to IQ scores. disorders who are functioning at similar male with the full mutation. Intellectual abilities range from nor- intellectual levels.6,7 In general, behav- mal to significant mental retardation, ioral difficulties can be separated into Premutation and the majority of females with a full a few symptom clusters. Features of Both females and males with a CGG re- mutation have a normal or borderline attention-deficit/hyperactivity disor- peat number that ranges from 55 to IQ. The milder phenotype in affected fe- der, including hyperactivity, inatten- 200 are considered to carry a premu- males correlates with the degree of X tiveness, distractibility, restlessness, tation. The prevalence of a premuta- inactivation of the X chromosome that and impulsivity, are present in 80% of tion has been estimated to be approx- contains the CGG expansion during ly- patients with fragile X syndrome. Af- imately 1 in 259 in females and 1 in 813 onization. A more severe phenotype fected children also can exhibit in males. People carrying the premuta- would be anticipated when there is anxiety-related symptoms including tion originally were believed to be clin- skewed X inactivation (eg, when the obsessive-compulsive–like and perse- ically normal, because the FMR1 gene majority of X randomly verative behaviors. Emotional lability is not methylated with a CGG repeat inactivated are those with a normal is common. Aggressive and self- number below 200, which results in CGG repeat number), thus preferen- injurious behaviors can occur, related FMRP activity. However, it is now rec- tially activating the X chromosome to a difficult temperament, with irrita- ognized that carriers of a premutation with an expanded CGG repeat number. bility and frequent temper tantrums. can present with 1 or more distinct

996 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS clinical disorders: mild cognitive of twinning also exists for conceptions TABLE 1 Risk of Expansion to a Full Mutation and/or behavioral deficits; primary in a woman with a premutation. in Male Offspring Based on the CGG Repeat Number in the Mother1,34 ovarian insufficiency (POI); and a Recently, a new phenotype that devel- CGG Repeat Risk for Expansion to neurodegenerative disorder in older ops in the later years of the majority of Number a Full Mutation, % adult premutation carriers, especially adult men who carry a premutation 59–69 37 males, called fragile X–associated (rarely reported in female premuta- 70–79 65 80–89 70 tremor/ataxia syndrome (FXTAS). In tion carriers) has emerged, desig- 90–99 95 contrast to decreased messenger RNA nated FXTAS.18,19 A progressive inten- Ն100 100 (mRNA) in people with a full mutation tion tremor develops after 50 years of and absence of FMRP, mRNA levels are age and is typically followed by ataxia. elevated and FMRP is present in people Associated features include a periph- number of CGG repeats in a female with a premutation. eral neuropathy; parkinsonian mani- with a premutation has the potential to festations; autonomic dysfunction A minority of female carriers of a pre- increase through several generations such as incontinence, impotence, and mutation have mild physical features of a family, the risk of expansion to a orthostatic hypotension; progressive of fragile X syndrome, which can in- full mutation also increases. cognitive impairments that involve clude prominent ears or hypermobile A premutation will be transmitted to finger joints. Emotional problems also loss of memory and deficits in execu- tive function; and psychological fea- all female offspring of a male with a may be present, including anxiety, ob- tures including disinhibition, anxiety, premutation. In these females, the CGG sessional thinking, schizotypy, and/or mood lability, irritability, outbursts, repeat number is similar to their fa- depression. It was observed recently depression, and isolation. Some pa- thers’ repeat number or may expand that depression and interpersonal tients progress to having . This slightly. However, the CGG repeat num- sensitivity were more likely to occur neurodegenerative disorder seems ber may undergo expansion when a fe- in females with a premutation with male with a premutation reproduces, pathogenetically distinct from fragile more than 100 CGG repeats than in which could result in an offspring with X syndrome and is probably related to those with fewer repeats.12 These a full mutation and fragile X syndrome. FMR1 messenger RNA levels that are emotional findings are likely to rep- A premutation in a male will not be elevated in premutation carriers. resent a mild form of the anxiety and transmitted to his male offspring, be- FXTAS has not been observed in males perseverative thinking that occurs in cause the son inherits his father’s Y with a full mutation. Maternal grandfa- chromosome. those with a full mutation and may be thers of affected males should be coun- the result of a mild deficit in FMRP seled and evaluated as appropriate for Who Should Be Tested for Fragile X found in the upper half of the premu- adult-onset movement disorders. Syndrome tation range. Males with a premutation The expansion of the number of CGG are prone to have attentional problems, Because children with fragile X syn- repeats occurs during reproduction in executive dysfunctions, social deficits, drome may not have apparent physi- a female with a premutation. This may and obsessive-compulsive behavior.13 cal features, any child who presents be a small expansion to a slightly with developmental delay, border- A disorder unique to female carriers of larger CGG repeat number in the pre- line intellectual abilities, or mental a premutation is POI (previously re- mutation range, or it may result in a retardation or has a diagnosis of au- ferred to as premature ovarian failure massive expansion into a full mutation. tism without a specific etiology [POF]), in which there is cessation of The risk of expansion to a full mutation should undergo molecular testing menses before 40 years of age.14–17 is determined by the size of the moth- for fragile X syndrome to determine This disorder is seen in approximately er’s premutation. As the CGG repeat the number of CGG repeats (Fig 1). 20% of women who carry a premuta- number increases, so does the risk of Approximately 2% to 6% of these pa- tion , in contrast to approxi- expansion to a full mutation (Table 1). tient populations will be found to have mately 1% in the general population. Therefore, the larger the number of re- an FMR1 mutation. The family should Subclinical ovarian dysfunction that peats, the more likely it will expand to a be made aware of the implications of leads to elevated follicle-stimulating full mutation in an offspring. To date, the testing for other family members hormone levels is seen in another 25% no offspring with a full mutation has and given the option of genetic coun- of adult women younger than 40 years been described when the CGG repeat seling before testing. Array compara- with a premutation. An increased risk number is less than 59. Because the tive genomic hybridization (or array

PEDIATRICS Volume 127, Number 5, May 2011 997 tion allele (55–200 CGG repeats), developmental testing may be indicated, and in older people, moni- toring is warranted for POI and FXTAS.

Management of a Child With Fragile 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 behavioral problems. Establishing a diagnosis of fragile X syndrome also will allow par- ents and/or caregivers to gain an un- derstanding of the disorder and how it affects the child’s development and be- havior. Diagnosis also will allow the family to focus on appropriate man- agement strategies that will maxi- mize their child’s potential. Formal assessment tools are available to assist with a behavior-management plan. Current approaches to therapy are supportive and symptom based. Psychopharmacologic intervention to modify behavioral problems in a child with fragile X syndrome may represent an important adjunctive therapy when combined with other FIGURE 1 Testing algorithm for fragile X syndrome and FMR1-related disorders. a Adults to be considered for supportive strategies including FMR1 molecular testing. (Adapted with permission from Saul RA, Tarleton JC. FMR1-related disorders. speech therapy, occupational ther- GeneReviews [online]. October 28, 2010. Available at: www.ncbi.nlm.nih.gov/books/NBK1384. Copy- apy, special educational services, right, University of Washington, Seattle, 1997–2010.) and behavioral interventions. Medi- cation management may be indi- testing) should also be considered. dren with isolated attention-deficit/ cated to modify attentional deficits, Phenotypic checklists have also been hyperactivity disorder. problems with impulse control, created for use in males with develop- and hyperactivity. Anxiety-related When evaluating a family with fragile mental delay of undetermined etiology symptoms, including obsessive- X syndrome, questions also should to help identify candidates for fragile X compulsive tendencies with perse- molecular testing. These checklists address whether there are people verative behaviors, also may be slightly increase the diagnostic yield, with mild emotional and/or learning present and require medical inter- especially when used in concert with problems, POI, and/or features of FX- vention. Emotional lability and epi- targeted family fragile X history TAS. Because people with a premuta- sodes of aggression and self-injury questionnaires. Fragile X testing tion are at risk of having these may be a danger to the child and oth- should also be considered in pa- conditions, molecular testing is sug- ers around him or her; therefore, the tients in whom there is suspected, gested for asymptomatic siblings of use of medication(s) to modify these but not molecularly proven, Sotos a child with fragile X syndrome and symptoms also may significantly im- syndrome or Prader-Willi syndrome. for other family members at risk of prove an affected child’s ability to par- On the other hand, fragile X testing, carrying the mutation. In family ticipate more successfully in activities is not routinely warranted for chil- members found to have a premuta- in home and school settings.

998 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS

Several classes of medications alone exists that is specifically directed at nizations and through contact with par- or in combination have proven to be improving cognitive ability in patients ents who have a similarly affected child. beneficial in managing behavior prob- with fragile X syndrome. However, be- The mother of a child with an FMR1 mu- lems in fragile X syndrome.7,20 Stimu- cause excessive mGLuR signaling plays tation is almost always a carrier of a lants target hyperactivity, inattention, a role in the fragile X syndrome pheno- premutation or full mutation. Females and impulsivity, and two-thirds to type, drugs that target mGLuR may be who are premutation carriers may three-quarters of symptomatic chil- an effective treatment in this disorder. have inherited the premutation from dren with fragile X syndrome benefit As more information regarding spe- their father or from their mother who from the use of . How- cific dendritic functions of FMRP are also carries a premutation. Women ever, in some affected people, stimu- elucidated, pharmacologic investiga- with a premutation are at risk of pre- lants may exacerbate anxiety, mood la- tions will likely be designed to address mature ovarian insufficiency and at bility, or aggressive tendencies. The specific neurochemical and synaptic small risk of FXTAS. They carry a 50% ␣-2-adrenergic agonists and deficits generated by the absence of risk of transmitting an abnormal gene, have been effective in treat- FMRP, targeting cognitive deficits which either contains a premutation ing hyperactivity, hyperarousal to sen- and also leading to improvements in copy number (55–200) or a full muta- sory stimuli, impulsivity, and aggressive behavior.7,25 tion (Ͼ200) in each pregnancy. Rarely, behaviors in approximately 70% of Factors in the environment also may a decrease in the number of CGG re- young boys with fragile X syndrome. influence adaptive behaviors, cogni- peats has been reported when the ab- These agents may be especially helpful in tive abilities, and behavioral symp- normal allele is transmitted from a a child who is younger than 5 years and toms of patients with fragile X syn- woman with a premutation to her does not tolerate or respond to stim- drome. For instance, in 1 study, daughter. The risk of expansion of a ulants. Clonidine also is effective for behavioral symptoms in children premutation in a mother to a full mu- the management of sleep distur- with fragile X syndrome who resided tation in her offspring correlates with bances,21 and may be in a nurturing home environment the number of CGG repeats in her mu- beneficial for regulating sleep displayed few autistic behaviors, bet- tation. Therefore, the higher the num- patterns.22 ter adaptive behavior, and higher ber of repeats in the mother, the Selective serotonin-reuptake inhibi- IQ.26 greater likelihood of expansion to a full tors can be useful in the management mutation in her offspring (Table 1). of mood disorders, anxiety, obsessive- Males who are premutation carriers compulsive behaviors, tantrums, and Fragile X syndrome and FMR1-related are referred to as transmitting males. aggression in people with fragile X syn- disorders (ie, POI and FXTAS) are inher- During reproduction, all of their drome. Atypical gener- ited in an X-linked dominant manner daughters will inherit a premutation, ally are reserved for people with frag- with often complex expression. Genetic but their sons will not inherit the pre- ile X syndrome who exhibit more counseling is recommended for all fam- mutation, because they inherit a Y extreme behaviors, particularly ag- ily members who are affected or at risk chromosome. All daughters of trans- gression, marked mood lability, self- of having a premutation or an offspring mitting males are unaffected premuta- injury, and other undesired behaviors. with a full mutation. Genetic counseling tion carriers. Transmitting males also Parent reports of improvement in is critical to provide information regard- need to be aware of the risk of devel- mood stabilization, attention, and aca- ing the inheritance pattern and variabil- oping FXTAS after the fifth decade of demic performance have been de- ity of the clinical phenotype in people be- life. scribed with , which ing affected with both a full mutation and Males with a full mutation, in most in- should be used at low doses to avoid premutation and to offer the option of stances, have mental retardation and agitation induced by higher doses.23 pursuing molecular testing. Options for decreased fertility. The FMRP plays a However, adverse effects can include reproductive planning can be discussed role in , and in 1 excessive weight gain, sedation, nau- in of family planning for study it was found that in later stages sea, constipation, diabetes, and tar- adults at risk of having an affected child. of spermatogenesis, men with fragile X dive dyskinesia.24 In addition to seeking help from profes- syndrome had significantly malformed Current psychopharmacologic ther- sionals who are knowledgeable of the spermatids and a reduction in nor- apy for fragile X syndrome is support- condition, information to assist families mally differentiated spermatids, which ive or symptom-based, and no therapy also can be obtained from support orga- may cause reduced fertility. A full

PEDIATRICS Volume 127, Number 5, May 2011 999 mutation cannot be maintained dur- and established the potential feasi- recommendations for evaluating at- ing spermatogenesis; therefore, the bility of such a screening process.31 risk family members. sperm contains only expanded FMR1 Various policy issues still need to be Health care providers should ensure gene CGG repeat sizes in the premuta- considered.32 that children with fragile X syndrome tion range. are afforded the standard care for all Both males and females can have THE PRENATAL VISIT children as outlined in the American mosaicism as a result of either full In some instances, pediatricians may Academy of Pediatrics “Recommenda- mutation/premutation mosaicism or be called on to counsel an expectant tions for Preventive Pediatric Health methylation/unmethylation mosaicism. couple whose fetus has been deter- Care”33 and specific fragile X syndrome In men, only a premutation will be mined to have fragile X syndrome or health supervision guidelines accord- transmitted to their female offspring.27 when there is a family history of the ing to their age (Table 2). Women with a full mutation are at 50% condition. In some settings, the pedi- risk of having male or female offspring atrician may be the primary re- HEALTH SUPERVISION FROM BIRTH with a full mutation. source for counseling parents and TO 1 MONTH: NEWBORNS (TABLE 2) Genetic counseling is more problem- family members. The pediatrician Examination atic when CGG repeats are in the should: 1. Examine the neonate for any ortho- range of 41 to 58 in the FMR1 allele. 1. Review the diagnostic studies that led pedic abnormalities, especially con- This is viewed as a “gray zone,” be- to establishment of the diagnosis. genital hip dysplasia and clubfoot. cause unstable alleles of this size have been reported, but expansion is 2. Explain the cause of fragile X syn- 2. Review the molecular testing re- unlikely. To date, the smallest repeat drome in the fetus and the potential sults with the family. In this age number to expand to a full mutation for a recurrence risk. group, the diagnosis will only have in a single generation was 59 CGG 3. Review the clinical manifestations, been made if there was a confirmed repeats. the variability seen in fragile X syn- family history or if it was previously established in utero. Although the Because fragile X syndrome can be dif- drome, and the long-term prognosis. typical phenotype of fragile X syn- ficult to diagnose in a child, various 4. Review currently available treat- drome generally will not be present studies have documented that 50% of ments and interventions. This dis- in the neonate, review the clinical families with males with fragile X syn- cussion should include the efficacy, manifestations and characteristic drome may have their second child be- potential complications and ad- patterns of growth and develop- fore the diagnosis is established in the verse effects, and costs or other ment and problems associated with first child.3,28–30 Families with an af- burdens of these treatments. this condition, which may become fected male have indicated that early 5. Explore, using a nondirective ap- more apparent with time. Evaluate diagnosis would have influenced their proach, the options available to the the neonate’s occipitofrontal cir- reproductive decision-making. After a family for treatment and rearing of cumference, which may be in- diagnosis was made, 73% of families the child. In cases of prenatal diag- creased, and begin to monitor reported that the diagnosis of fragile X nosis, this approach may include head-growth velocity. syndrome affected their decision to discussion of pregnancy continua- have another child, and 43% of the 3. Monitor for feeding difficulties and tion or termination, rearing the families surveyed had a second child symptoms of gastroesophageal child at home, foster care place- with a full mutation. Therefore, detec- reflux. ment, or adoption. tion of fragile X syndrome not only would enable at-risk families to re- It is strongly encouraged that this Anticipatory Guidance ceive accurate reproductive counsel- counseling be done in conjunction with 1. Review the support groups and ser- ing for the immediate and extended genetic counseling or referral to a ge- vices that are available to the child family but also could allow for appro- netic counselor or clinical geneticist to and family. Supply written materi- priate intervention beginning in in- provide a more in-depth discussion of als on fragile X syndrome and pro- fancy. Recently, a pilot study in South fragile X syndrome, including the asso- vide the address and telephone Carolina on newborn filter-paper ciated medical conditions, prognosis, number of organizations involved blood screens to perform testing for management strategies, recurrence in fragile X syndrome (eg, Na- fragile X syndrome was completed risk, future reproductive options, and tional Fragile X Foundation [www.

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TABLE 2 Fragile X Syndrome: Guidelines for Health Supervision Infancy to 1 y Early Childhood, Late Childhood, Adolescence to Early 1–5 y 5–12 y Adulthood, Ն13 y Newborn 1–6 mo 6–12 mo Examination Ocular 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 guidance Genetics j   k k Psychosocial l l l l l — Support groups     Early intervention, physical —     and 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 outlined in 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.

FragileX.org], FRAXA Research full mutation, or refer for formal ge- 3. Feeding problems, which are com- Foundation [www.FRAXA.org]). netic counseling to address these mon in infancy, and the presence of 2. Discuss resources available for issues. vomiting secondary to gastro- support, such as family clergy, men- esophageal reflux. tal health professionals, families HEALTH SUPERVISION FROM 1 who have an affected child residing MONTH TO 1 YEAR: INFANCY Anticipatory Guidance in the area, and friends. (TABLE 2) 1. Monitor growth parameters 3. Discuss how and what to tell family Examination closely. members and friends about the ne- 2. If feeding problems are severe, pur- Early growth and development may onate’s condition. sue diagnostic evaluations to deter- be normal, although neurologic ab- 4. Review the recurrence risk for subse- mine if they are the result of oral normalities and delayed develop- quent pregnancies; discuss options motor problems and/or gastro- ment may be present. Monitor the in- for family planning, including prena- esophageal reflux. If gastroesopha- fant for the following problems: tal and preimplantation genetic diag- geal reflux is identified, initiate ap- nosis; or refer for formal genetic 1. Hypotonia that frequently results in propriate management strategies counseling to address these issues. mild motor delay. or refer the infant for further eval- 5. Review the family history regarding 2. Irritability, which is usually second- uation by a pediatric gastroenterol- evaluation of other family members ary to sensory problems, including ogist. If oral motor problems exist, at risk of having a premutation or tactile hypersensitivity. refer the infant to an appropriate

PEDIATRICS Volume 127, Number 5, May 2011 1001 interventionist to initiate feeding (23% of affected children). Monitor ment, and absent joint attention therapy. the child’s audiologic status yearly. may be present before 3 years of 3. Review the available resources to 6. Receptive and expressive communi- age and necessitate further evalua- provide the infant with early- cation should be monitored closely, tion. Excessive sensory stimulation intervention services and assist the because language delay is usually should be avoided when possible, individualized family service plan evident by 2 years of age. An occu- including exposure to large crowds team in providing the most appro- pational therapy evaluation also and loud noises; earphones can be priate services to maximize the in- may be indicated and should in- used in such settings to allow the fant’s developmental potential. Par- clude an assessment of sensory in- child to listen to a favorite tape or ents should consider applying for tegration abilities. A complete psy- calming music to avoid behavioral Supplemental Security Income chological evaluation that includes outbursts. Significant behavior (SSI) through the Social Security IQ testing is an important part of the problems, such as tantrums, oppo- Administration. developmental evaluation of the sitional behavior, or severe hyper- preschool-aged child with fragile X activity, usually benefit from inter- HEALTH SUPERVISION FROM 1 TO 5 syndrome. Affected children re- vention by a psychologist or other YEARS: EARLY CHILDHOOD quire early developmental services behavioral specialist. Behavioral in- (TABLE 2) to facilitate language, motor, and tervention techniques that empha- cognitive skills. These services are size the importance of decreasing Examination mandated by federal law and excessive sensory stimuli and using 1. Perform an ophthalmologic evalua- should be followed by enrollment in positive behavioral reinforcement tion or arrange for ophthalmologic a developmental preschool and and the use of behavioral charting referral to check for strabismus supplemented with special educa- are beneficial. and refractive errors, especially hy- tion services. Occupational and 8. Psychopharmacologic interven- peropia and astigmatism, which speech-language therapy should be tions can be helpful. The use of are seen in 25% to 50% of affected incorporated into the program and medication to treat hy- children. Also monitor for ptosis should include continued attention peractivity, short attention span, and nystagmus, which are seen to language, motor, and cognitive and impulsivity decreases symp- occasionally. skills up to and including kindergar- toms in approximately 60% to 70% 2. Evaluate the child for orthopedic ten. Computer technology with soft- of affected children but may be problems related to connective tis- ware programs that enhance lan- more effective for a child who is of sue dysplasia, such as pes planus guage skills and early academic school age than of preschool age. At (80% of affected children), hyper- abilities, including reading and a younger age, antihypertensive mobile joints, and . Prona- mathematics, can be incorporated medications, such as clonidine or ted feet require treatment with or- into program- guanfacine, may have a better calm- thotics if a gait disturbance exists ming. Inclusion in a preschool set- ing effect and improve hyperactivity or there is uneven wearing of ting is achievable with appropriate and hyperarousal. For treatment of shoes. supports. anxiety, social phobia, obsessive- compulsive tendencies, depression, 3. Examine the child for inguinal her- 7. Monitor the child’s emotional and and aggression, use of a selective nias, especially at 1 to 3 years of behavioral status closely. Tantrums and hyperactivity frequently de- serotonin-reuptake inhibitor is safe age. velop in the second year of life, es- and can be effective. Monitoring for 4. Assess the child’s history for sei- pecially related to transitioning and the development of akathisia (mo- zures or staring episodes and ob- excessive sensory stimuli. Evidence tor restlessness) is important. In tain an electroencephalogram if of anxiety and depression as well as addition, in the presence of severe clinically indicated. the presence of aggression and mood instability and/or aggression 5. Monitor the child for recurrent oti- obsessive-compulsive behaviors that are unresponsive to a selective tis media (60%–80% of affected may develop during this time pe- serotonin-reuptake inhibitor or children), which could be associ- riod. Manifestations of autism, such stimulant medication, use of an ated with conductive hearing loss, as hand-flapping, self-injury, poor atypical agent to pro- and also for recurrent eye contact, lack of social engage- vide mood stabilization may be indi-

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cated. Approximately 10% of people 1. Determine if behaviors such as hy- 2. Girls with the full mutation should with fragile X syndrome develop peractivity, aggression, self-injury, be monitored for the development psychotic symptoms often associ- and tantrums warrant medication of precocious puberty, which has ated with severe paranoia, which management. been reported occasionally. Al- also may lead to aggressive 2. Seizures are an important clinical though the cause in most instances behavior. manifestation that occurs in ap- is unknown, hypothalamic dysfunc- 9. Linear growth during this period proximately 20% of people with tion has been described with fragile should be monitored closely, and lin- fragile X syndrome and usually have X syndrome and may be the cause ear growth velocity should be similar their onset in early childhood. Ap- of precocious puberty. to that of unaffected children. propriate evaluation and treatment 3. Continuing to monitor the child’s is indicated when suspicion of sei- 10. Structural changes of the face developmental status is critical for zures is present. making certain that cognitive, may start to become evident in speech and language, and motor preschool years and include a 3. Auscultation of the heart should be needs are being addressed. Being long face, high forehead, high performed and blood pressure provided with reports of interval arched palate, and prominent should be obtained at all clinic vis- progress in school is useful in de- ears. Facial changes can result in its. The presence of a murmur or termining the effectiveness of the dental crowding and malocclu- click should indicate the need for child’s programming and whether sion, and regular dental evalua- further evaluation by a pediatric modifications or further evaluation tion is recommended. cardiologist, and elevated blood pressure will require monitoring are indicated. 11. Occasionally, in affected children, and a determination of whether 4. Hyperactivity frequently will persist obstructive sleep apnea occurs, medical treatment is indicated. throughout childhood and is pres- which may be related, in part, to 4. Delays in toilet-training can be ent in approximately 70% to 80% of facial changes but also can be the helped by behavioral interven- affected boys and 30% to 50% of result of the connective tissue dys- tions including the use of a music girls with a full mutation. Address- plasia and hypotonia of facial and video to facilitate toilet-training ing this problem behaviorally pharyngeal muscles. Excessive for people with developmental and/or in combination with medica- snoring, restless sleep, or fatigue .6(p291) tion management may be indicated. during the day should signal the 5. Monitor the child for obsessive- need for further evaluation of 5. Review the future reproductive compulsive behaviors, especially be- the child’s sleep problem with plans of the parents and discuss re- cause they may blend in with perse- evaluation of adenoidal size and currence risk and family-planning verative or repetitive behaviors and the child’s sleep pattern by using options when indicated. not be recognized. Anxiety—espe- polysomnography. HEALTH SUPERVISION FROM 5 TO cially —frequently is 12. Delayed toilet-training is common 12 YEARS: LATE CHILDHOOD present, particularly in children during this age range and is likely (TABLE 2) who do not have hyperactivity or im- to reflect the child’s cognitive 1. Macro-orchidism usually begins to pulsivity. Pursuing appropriate status. develop at approximately 9 years of management strategies to address age, and the testes will increase in the child’s emotional needs is im- Anticipatory Guidance size throughout puberty (mean tes- portant for effective adaptation in The pediatrician should review the ticular volume in adulthood: ϳ50 the home and school settings. child’s preschool placement and ancil- mL). Testicular volume should be 6. Cognitive impairments result in lary services that complement the pro- measured with an , and mental retardation in most boys gram. Inclusion with typically develop- boys should be assessed for the pres- who have a full mutation that is fully ing children should be considered ence of a hernia, which occurs in ap- methylated (average IQ: ϳ40). Oc- when appropriate and may require su- proximately 15% of males with a full casionally, males with a full muta- pervision in that setting. Consider a mutation. Assure the parents that tion are higher functioning because formal developmental evaluation and macro-orchidism has no relation to of incomplete methylation of FMRP discuss the role of behavior/psycho- sexual function and that it is not a as a result of mosaicism. Approxi- logical intervention when indicated. sign of precocious puberty. mately 50% of females with a full

PEDIATRICS Volume 127, Number 5, May 2011 1003 mutation have cognitive deficits (IQ HEALTH SUPERVISION FROM 13 TO ciency, whereas females with full mu- range: 70–84). Recognition of cog- 21 YEARS OR OLDER: tations are not. Males who are pre- nitive impairments and adaptive ADOLESCENCE TO EARLY mutation carriers have no known functioning deficits should signal ADULTHOOD (TABLE 2) fertility problems. the need for pursuing appropriate 1. Hyperactivity may decrease during 6. Determine if behavioral problems support services in the school set- adolescence, but attentional prob- continue to represent a concern, ting to meet the child’s needs. lems and impulsivity frequently and pursue behavioral/psychologi- 7. In addition to delayed toilet- persist and may continue to need to cal intervention if indicated. training, enuresis is common in be addressed behaviorally and 7. Discuss the availability and need for both boys and girls with fragile X medically. vocational training and group home syndrome. Although affected chil- 2. Assess adolescents for seizures, es- placement if appropriate. dren are not considered to be at in- pecially atypical seizures, particu- 8. Monitor for a cardiac murmur or creased risk of recurrent urinary larly if intellectual performance is click; if either is heard, pursue a tract infections, the connective tis- decreasing, although seizures tend cardiology evaluation (see recom- sue dysplasia may predispose to to decrease during this time period. mendation 1 in “Health Supervision dilatation of the ureters and vesi- 3. Reassure parents that macro- in Adulthood”). coureteral reflux.6(p27) Further orchidism will persist. Males (espe- 9. Facilitate transition to adult medi- evaluation of the urinary tract cially with a premutation or mosa- cal care as appropriate or desired. through radiographic and ultra- icism) and females with fragile X 10. Agencies that serve people with sonographic studies is indicated in syndrome can reproduce. Only a developmental disabilities are the presence of a urinary tract in- premutation will be present in the present in most states and may fection, and referral to a nephrolo- sperm of a male who has a full mu- provide respite for parents, adult gist or urologist is indicated if uri- tation, in contrast to other tissues, day care programs, and personal nary tract infections are recurrent because a full mutation cannot be assistance and nursing services in nature or a structural abnormal- maintained in spermatogenesis; as needed. ity or reflux is identified. Behavioral therefore, fertility is decreased in strategies should be implemented males. HEALTH SUPERVISION IN in the presence of nighttime enure- 4. The adolescent growth spurt may ADULTHOOD (TABLE 2) sis. In addition, treatment of enure- be slightly less compared with un- During the transition from pediatric to sis may also require the use of affected children, although the adult medical care, the pediatrician behavior-modification techniques timing is normal. Psychosocial de- can be a valuable source of informa- and an alarm system. If unsuccess- velopment, physical sexual devel- tion to the affected person’s new ful, medication management with opment,35 and fertility should be primary care physician and/or agents such as imipramine, oxybu- discussed, as well as the need for obstetrician/gynecologist. The follow- tynin (an anticholinergic agent), or appropriate supervision and birth ing information about fragile X syn- desmopressin acetate (an analog control. Counseling should be tai- drome can be communicated to facili- antidiuretic hormone) should be lored appropriately to cognitive tate the care of an affected adult: considered. Only occasionally will level. 1. Mitral valve prolapse occurs in ap- children require medication for 5. Genetic mechanisms responsible for proximately 50% of affected adults. this problem. Macro-orchidism will fragile X syndrome should be dis- Mild aortic root dilatation also has be maintained throughout adult life cussed with people with full muta- been reported, although it has not and does not require intervention. tions and premutations, and the risk been documented to enlarge. In ad- 8. Because of the connective tissue of having an affected offspring should dition, hypertension is common in dysplasia, children should be moni- be reviewed. Males who are of repro- adulthood. tored for scoliosis, which occurs in ductive age and have nonmosaic full 2. Up to 20% of women with a premu- approximately 20% of affected chil- are infertile. Females with tation will develop premature dren. However, when present, it is full mutations are fertile. Females before 40 years of age. usually mild and does not require with premutations are at increased 3. There is a greater risk of emotional treatment. risk of premature ovarian insuffi- problems in affected females, espe-

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cially at times of hormonal with a premutation, warrants Stephen R. Braddock, MD changes or estrogen deficiency, close monitoring for symptoms, Gregory M. Enns, MB, ChB Jeffrey R. Gruen, MD such as menopause, the postpar- especially when approaching 50 James M. Perrin, MD tum period, and during menstrual years of age. Robert A. Saul, MD Beth Anne Tarini, MD periods. People with fragile X syndrome and 4. Genetic counseling should be pro- FMR1–related disorders face chal- FORMER COMMITTEE ON GENETICS vided to review the risk for having lenges throughout their entire lives. MEMBER an offspring with either a premuta- Therefore, coordinating medical, de- Joseph H. Hersh, MD tion or full mutation and options velopmental, and behavioral services LIAISONS available for family planning. An in- with available community resources James W. Hanson, MD – American College of creased risk of twinning also can maximize the potential for affected should be discussed with females people and minimize the stressors Michele Ann Lloyd-Puryear, MD, PhD – Health who have a premutation. faced by other family members. Resources and Services Administration Thomas J. Musci, MD – American College of 5. Men and, to a lesser degree, women LEAD AUTHORS Obstetricians and Gynecologists with a premutation are at in- Sonja Ann Rasmussen, MD, MS – Centers for Joseph H. Hersh, MD Disease Control and Prevention creased risk of developing FXTAS af- Robert A. Saul, MD ter 50 years of age. Awareness of COMMITTEE ON GENETICS, 2009–2010 STAFF this risk, particularly in a man Howard M. Saal, MD, Chairperson Paul Spire REFERENCES

1. Saul RA, Tarleton JC. FMR1-related disor- ences and perceptions. Pediatrics. 2003; tremor/ataxia syndrome in a premutation ders. GeneReviews [online]. October 28, 111(2):407–416 carrier population. JAMA. 2004;291(4): 2010. Available at: www.ncbi.nlm.nih.gov/ 11. Nowicki ST, Tassone F, Ono MY, et al. The 460–469 books/NBK1384. Accessed November 18, Prader-Willi phenotype of fragile X syn- 19. Hagerman RJ, Leavitt BR, Farzin F, et al. 2010 drome. J Dev Behav Pediatr. 2007;28(2): Fragile-X-associated tremor/ataxia syn- 2. Penrose LS. A Clinical and Genetic Study of 133–138 drome (FXTAS) in females with the FMR1 1280 Cases of Mental Defect. London, United 12. Hunter JE, Abramowitz A, Rusin M, Sherman premutation. Am J Hum Genet. 2004;74(5): Kingdom: Her Majesty’s Stationery Office; SL. Is there evidence for neuropsychologi- 1051–1056 1938. Special Report Series, Medical Re- cal and neurobehavioral phenotypes 20. Hagerman RJ. Medical follow-up and phar- search Council, No. 229 among adults without FXTAS who carry the macotherapy. In: Hagerman RJ, Hagerman 3. Martin JP, Bell J. A pedigree of mental de- FMR1 premutation? A review of current lit- PJ, eds. Fragile X Syndrome: Diagnosis, fect showing sex-linkage. J Neurol Psychia- erature. Genet Med. 2009;11(2):79–89 Treatment, and Research. 3rd ed. Balti- try. 1943;6(3–4):154–157 13. Farzin F, Perry H, Hessl D, et al. Autism spec- more, MD: Johns Hopkins University Press; 4. Lubs HA. A marker X chromosome. Am J trum disorders and attention-deficit/ 2002:287–338 Hum Genet. 1969;21(3):231–244 hyperactivity disorder in boys with the frag- 21. Prince JB, Wilens TE, Biederman J, Spencer 5. Warren ST, Sherman SL. The fragile X syn- ile X premutation. J Dev Behav Pediatr. 2006; TJ, Wozniak JR. Clonidine for sleep distur- drome. In: Scriver CR, Beaudet AL, Sly WS, 27(2 suppl):S137–S144 bances associated with attention-deficit hy- Valle D, Vogelstein B, eds. The Metabolic and 14. Bretherick KL, Fluker MR, Robinson WP. peractivity disorder: a systematic review of Molecular Bases of Inherited Disease. New FMR1 repeat sizes in the gray zone and high 62 cases. J Am Acad Child Adolesc Psychia- York, NY: McGraw-Hill; 2001:1257–1289 end of the normal range are associated try. 1996;35(5):599–605 6. Hagerman RJ, Hagerman PJ, eds. Fragile X with premature ovarian failure. Hum Genet. 22. Jan JE, O’Donnell ME. Use of melatonin in the Syndrome: Diagnosis, Treatment, and Re- 2005;117(4):376–382 treatment of paediatric sleep disorders. J search. 3rd ed. Baltimore, MD: Johns Hop- 15. Bodega B, Bione S, Dalpra L, et al. Influence Pineal Res. 1996;21(4):193–199 kins University Press; 2002 of intermediate and uninterrupted FMR1 23. Hagerman RJ. Lessons from fragile X re- 7. Hagerman RJ, Berry-Kravis E, Kaufmann CGG expansions in premature ovarian fail- garding neurobiology, autism and neurode- WE, et al. Advances in the treatment of ure manifestation. Hum Reprod. 2006;21(4): generation. J Dev Behav Pediatr. 2006;27(1): fragile X syndrome. Pediatrics. 2009; 952–957 63–74 123(1):378–390 16. Nelson LM, Covington SN, Rebar RW. An 24. Garber KB, Visootsak J, Warren ST. Fragile X 8. Bear MF, Huber KM, Warren ST. The mGluR update: spontaneous premature ovarian syndrome. Eur J Hum Genet. 2008;16(6): theory of fragile X mental retardation. failure is not an early menopause. Fertil 666–672 Trends Neurosci. 2004;27(7):370–377 Steril. 2005;83(5):1327–1332 25. Wang LW, Berry-Kravis E, Hagerman RJ. 9. Warren ST, Nelson DL. Advances in molecu- 17. Nelson LM. Clinical practice: primary ovar- Fragile X: leading the way for targeted treat- lar analysis of fragile X syndrome. JAMA. ian insufficiency. N Engl J Med. 2009;360(6): ments in autism. Neurotherapeutics. 2010; 1994;271(7):536–542 606–614 7(3):264–274 10. Bailey DB Jr, Skinner D, Sparkman KL. Dis- 18. Jacquemont S, Hagerman RJ, Leehey MA, et 26. Glaser B, Hessl D, Dyer-Friedman J, et al. Bio- covering fragile X syndrome: family experi- al. of the fragile X-associated logical and environmental contributions to

PEDIATRICS Volume 127, Number 5, May 2011 1005 adaptive behavior in fragile X syndrome. Am J 30. Bailey DB Jr, Skinner D, Davis AM, Whit- tee on Practice and Ambulatory Medicine, Med Genet A. 2003;117A(1):21–29 marsh I, Powell C. Ethical, legal, and social Bright Futures Steering Committee. 27. Reyniers E, Vits L, De Boulle K, et al. The full concerns about expanded newborn Recommendations for preventive pediat- mutation in the FMR1 gene of male fragile X screening: fragile X syndrome as a proto- ric health care. Pediatrics. 2007;120(6): patients is absent in their sperm. Nat Genet. type for emerging issues. Pediatrics. 2008; 1376 1993;4(2):143–146 121(3). Available at: www.pediatrics.org/ 34. Sherman S. Clinical implications of gray- 28. Centers for Disease Control and Preven- cgi/content/full/121/3/e693 zone FMR1 alleles [abstract 308]. Pre- tion. Delayed diagnosis of fragile X 31. Saul RA, Friez M, Eaves K, et al. Fragile X sented at: American College of Medical syndrome: United States, 1990–1999. syndrome detection in newborns: pilot Genetics meeting; March 17–20, 2005; Dal- MMWR Morb Mortal Wkly Rep. 2002; study. Genet Med. 2008;10(10):714–719 las, TX 51(33):740–742 32. Ross LF, Acharya K. Policy considerations 35. Siebelink EM, deJong MD, Taal E, Roelvink 29. Skinner D, Sparkman KL, Bailey DB Jr. in designing a fragile X population L. Sexuality and people with intellectual Screening for fragile X syndrome: parent at- screening program. Genet Med. 2008; disabilities: assessment of knowledge, at- titudes and perspectives. Genet Med. 2003; 10(10):711–713 titudes, experiences, and needs. Ment Re- 5(5):378–384 33. American Academy of Pediatrics, Commit- tard. 2006;44(4):283–294

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