Fragile X syndrome: Management in children and adolescents

INTRODUCTION — The management of children and adolescents with fragile X syndrome (FXS) is individualized according to the child's cognitive and behavioral symptoms, strengths, and weaknesses [1,2]. (See 'Evaluation to determine extent of disease' below.)

Interventions may include individualized education programs, speech and language therapy, occupational therapy, behavior therapy, and pharmacotherapy. Few controlled trials have been performed to assess the effectiveness of these interventions in children with FXS [3,4]. However, they are effective in children with other cognitive or behavioral problems. (See "Intellectual disability (ID) in children: Management, outcomes, and prevention" and "Specific learning disorders in children: Educational management".)

The management of children and adolescents with FXS is discussed in this topic review. The clinical features, diagnosis, and prenatal screening are discussed separately. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents" and "Fragile X syndrome: Prenatal screening and diagnosis".)

GENETIC COUNSELING — Families of persons with FXS should be referred to a geneticist or genetic counselor for a detailed discussion of the inheritance of a fragile X messenger ribonucleoprotein 1 (FMR1) mutation and testing of other family members. FXS test results should be interpreted for the family according to the guidelines established by the National Society of Genetic Counselors and the American Society of Human Genetics [2,5]. Family members at risk for premutation or full mutation of FMR1 should receive information about possible emotional, neurologic, and reproductive problems (eg, premature ovarian insufficiency).

EVALUATION TO DETERMINE EXTENT OF DISEASE — Following initial diagnosis of FXS, children and adolescents should undergo a multidisciplinary evaluation to determine the extent of disease [1]. The evaluation should include:

●Complete developmental and educational assessments (including speech and language, academic, problem solving skills using visual information, fine motor, and gross motor) for special educational planning.

●Behavioral and psychology assessment to evaluate cognitive abilities, adaptive behavior, concentration or attention problems, anxiety, obsessive compulsive symptoms, aggression, and depression.

●Medical evaluation for presence of associated medical problems, including feeding problems, gastroesophageal reflux, hypotonia, joint laxity, mitral valve prolapse, seizures, strabismus, and recurrent otitis media. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents", section on 'Additional associated findings' and "Fragile X syndrome: Clinical features and diagnosis in children and adolescents", section on 'Seizures'.)

DEVELOPMENTAL AND EDUCATIONAL INTERVENTIONS — Children and adolescents with FXS usually have special educational needs and should be referred for early intervention (if less than 36 months of age) or special educational (if greater than 36 months of age) programs [6,7]. Children with FXS often have difficulties with mathematics and expressive language skills [8]. However, developmental strengths and weaknesses must be assessed on an individual basis [7]. Children with FXS and autism require additional educational interventions. The National Fragile X Foundation website contains detailed information in several languages on the recommended educational programs for children with FXS that can be downloaded. In addition, the use and efficacy of tablet-based cognitive and working memory training programs are under investigation in persons with FXS [9]. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)

BEHAVIORAL INTERVENTIONS — Behavioral interventions may be effective in promoting coping skills and reducing problematic behaviors (eg, aggression, stereotypic behaviors, self-injury) [7,10,11]. There are few empirical studies of the effectiveness of behavioral interventions for children and adolescents with FXS [12]. Treatment strategies are guided by the therapist's experience and understanding of factors associated with problematic behaviors [7,12]. These behaviors often are precipitated and reinforced by social and/or environmental events (eg, anxiety, sensory overload, change in routine, the amount of attention the child is receiving, etc) [7,13-16]. Environmental changes (eg, small class size, avoiding excessive stimulation, avoiding sudden changes) may reduce the frequency of problem behaviors [1,17]. In addition, individuals with FXS can be taught to recognize stressful situations and use self-calming techniques before responding inappropriately [7].

Behavioral interventions for children with intellectual disability and autism spectrum disorder are discussed in greater detail separately. (See "Intellectual disability (ID) in children: Management, outcomes, and prevention", section on 'Behavior intervention' and "Autism spectrum disorder in children and adolescents: Behavioral and educational interventions".)

Children and adolescents with FXS who have higher levels of function may benefit from counseling or psychotherapy to focus on anxiety reduction, socialization, and depression [12,18].

PHARMACOTHERAPY — Psychopharmacologic therapy may be necessary for children and adolescents with FXS and attention deficit hyperactivity disorder, anxiety, mood instability, or maladaptive behaviors (eg, perseveration, aggression, self-injury) that significantly affect social interaction and are not controlled with environmental or behavioral interventions. There is no specific therapy for enhancing cognitive abilities [4].

Psychopharmacologic intervention is individualized according to symptoms and must be closely monitored [1]. Specific agents may help with some problematic behaviors but exacerbate others [4].

There are few controlled studies evaluating the use of psychopharmacologic interventions in children and adolescents with FXS. Evidence to support their use is derived from observational surveys of clinical populations [12].

Hyperactivity and inattention — Inattention and hyperactivity in children with FXS over five years of age are typically treated with stimulants [4]. Observational studies suggest that stimulants are beneficial in approximately 70 percent of boys with FXS [4,19]. In a small, placebo-controlled crossover trial, methylphenidate in addition to behavioral interventions and individualized therapy was associated with improved teacher ratings of socialization skills and attention span [19]. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications".)

Benefits of stimulants may include increased attention span and decreased distractibility, motor activity, fidgeting, and impulsivity [4]. Adverse effects of stimulants may include appetite suppression, insomnia, moodiness, increased aggressiveness or irritability, and aggravation of anxiety or perseveration. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects'.)

In children younger than five years, stimulants may exacerbate irritability or other behavior problems. Nonstimulant therapies (eg, alpha-2 agonists such as guanfacine and clonidine) often are used in this age group to treat hyperactivity, inattention, and hyperarousal [4,12]. In observational studies, alpha-2 agonists are beneficial in approximately 60 to 70 percent of patients [4,20,21]. Adverse effects of alpha-2 agonists include decreased blood pressure and sedation [20]. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications".)

Other behaviors

●Anxiety, compulsive behaviors, and mood symptoms may be managed with antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). Observational studies suggest that treatment with SSRIs relieves anxiety in approximately 50 percent of patients with FXS [4,22]. However, approximately 20 percent of treated patients reported activation (restlessness, mood change, disinhibited behavior, aggression) with SSRIs [22]. (See "Pharmacotherapy for anxiety disorders in children and adolescents", section on 'SSRI/SNRI'.)

Benefits of SSRIs may include decreased obsessive-compulsive behaviors, decreased irritability, increased comfort in social situations, and ability to tolerate environmental stimuli [4]. Adverse effects may include activation, changes in appetite, insomnia, nausea, and suicidal ideation. (See "Pediatric unipolar depression and pharmacotherapy: Choosing a medication", section on 'Adverse side effects'.)

●Irritability, aggression, mood instability, and perseverative behaviors may respond to treatment with antipsychotic agents (eg, risperidone, aripiprazole) [4,12]. In controlled trials in children with autism, risperidone has been shown to be beneficial in controlling aggressive and aberrant behavior [23-25], and it is US Food and Drug Administration (FDA) approved for use in children above five years of age. Aripiprazole, which is US FDA approved for children over six years of age, also may target distractibility, anxiety, mood instability, and aberrant social behaviors.

Benefits of antipsychotics may include improved sleep and decreased anxiety, agitation, perseveration, and aggression [4]. Adverse effects may include sedation, nausea, constipation, dystonic and extrapyramidal reactions, gynecomastia, and weight gain [26]. (See "Autism spectrum disorder in children and adolescents: Pharmacologic interventions".)

Seizures — Seizures in children with FXS generally are controlled with a single antiseizure medication (eg, carbamazepine, valproate [valproic acid], lamotrigine, oxcarbazepine, zonisamide) [12]. Valproate also works as a mood stabilizer and can help with aggression or episodic dyscontrol in some children [27]. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

Phenytoin is usually avoided because it is associated with gingival hypertrophy, and it is difficult to manage dental problems in children with FXS because of their hypersensitivity. Phenobarbital and gabapentin may exacerbate behavior problems and also should be avoided in children with FXS.

Investigational therapies — A number of investigational therapies target biochemical pathways that are thought to play a role in the clinical manifestations of FXS [28], but the evidence for each of these therapies is at best weak or marginal. These therapies include:

●Metabotropic glutamate receptor 5 (mGluR5) antagonists – Excessive mGluR5 signaling is thought to contribute to some of the behavioral abnormalities and cognitive deficits of FXS [3,12,29]. In animal models, mGluR5 antagonists have demonstrated improvements in behavior and cognition; reduction of anxiety, depression, and seizures; and correction of underlying abnormal cellular processes such as aberrant cell signaling [3,30-32]. A small, randomized trial in 30 adult patients with FXS showed significant improvement on the Aberrant Behavior Checklist-Community Edition (ABC-C) score but only in the subset of seven patients with a fully methylated promoter [33,34]. Additional studies investigating the effect of mGluR5 antagonists on language learning also failed to show any significant result in three to six year-old children with FXS [35].

●Lithium – Lithium downregulates the phospholipase C signaling pathway that is used by mGluR5 and other receptors to activate dendritic translation, and it has the potential to correct excessive dendritic protein synthesis in FXS [12]. A small, open-labeled trial of lithium in 15 males with FXS (6 to 23 years) found significant improvement in behavioral functioning, adaptive behavior, and verbal memory [36]. Larger randomized trials are needed to confirm these results.

●Minocycline – Matrix metalloproteinases (MMP) modulate synaptic physiology and plasticity, and MMP9 levels are elevated in the hippocampus in patients with FXS [37]. Open-label studies of minocycline in patients with FXS demonstrated improvements in language, attention, social communication, anxiety, and behavior [38,39]. A subsequent randomized trial of minocycline in 55 individuals (aged 3.5 to 16 years) showed improvement on the Clinical Global Impression Scale [40]. Another clinical trial in which minocycline was combined with lovastatin in 22 persons showed significant improvement in the ABC-C global score [41]. However, the potential benefits of this therapy should be weighed against the potential side effects of prolonged intake of antibiotics, including diarrhea and discoloration of the teeth in young infants, especially in children, who would require long-term treatment. In addition, minocycline treatment can increase antinuclear antibody levels, which can cause a lupus-like syndrome. This effect is reversed when minocycline is discontinued [37].

●Gamma-aminobutyric acid (GABA) system agonists – GABA is the primary inhibitory neurotransmitter in the central nervous system. The GABA system is downregulated in FXS [42]. Social function and behavior, but not irritability, improved in patients with FXS in a phase II trial of the GABA agonist arbaclofen [43]. In two subsequent phase III trials, adolescents and adults with FXS who received arbaclofen did not show behavioral improvement compared with patients who received placebo, but children 5 to 11 years of age had a significant improvement on the Aberrant Behavior Checklist-Community Edition (ABC-CFX) [44]. A subsequent phase II study with ganaxolone, a GABA-A receptor agonist, did not show significant improvements in the outcome measures in the overall study population (6 to 17 years).

●Chloride importer antagonists – As noted above, GABAergic signaling is deficient in FXS [42]. However, GABA actions are shifted from inhibitory to excitatory with elevated levels of intracellular chloride seen in many disorders, including FXS. Bumetanide, a diuretic NKCC1 chloride importer antagonist that decreases intracellular chloride and has shown efficacy in treating autism, improved autistic features in a patient with FXS [45].

●L-acetylcarnitine (LAC) – LAC, the acetylated form of carnitine, inhibits expression of the FXS-associated fragile site, FRAXA [46]. Two small, randomized trials have examined the efficacy of LAC in treating the psychological, learning, behavioral (eg, hyperactivity), and socialization problems in patients with FXS and essentially found no differences compared with placebo [47].

●Ampakines (positive AMPA receptor modulators) – Excessive mGluR activity contributes to reduced synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and excessive internalization of AMPA receptors [12]. Reduced AMPA receptor signaling is another potential target for therapy. In a controlled trial, treatment with CX516 (an ampakine) had no effect on cognitive function in a cohort of subjects with FXS [48].

●Cannabinoid receptor antagonists – Activation of mGluR5 enhances production of endocannabinoids, leading to depression of excitatory and inhibitory transmission and amplification of the mammalian (mechanistic) target of rapamycin (mTOR) signaling pathway mediated via cannabinoid receptor 1 (CNR1, also called CB1R). In a mouse model, CNR1 blockade with rimonabant normalized cognitive performance, nociception, and seizure susceptibility [49]. A phase III trial, using a transdermal cannabidiol gel, demonstrated some benefits in patients with full methylation of the FMR1 gene [50].

●mTOR inhibitors – Enhanced mTOR signaling is thought to contribute to some of the cognitive deficits seen in patients with FXS [51]. Both acute and chronic administration of an mTOR inhibitor, temsirolimus, prevented memory impairment in a murine model [49].

In addition to pharmacologic investigational therapies that target biochemical pathways, other therapeutic avenues using cellular and animal models are under exploration:

●Since FXS is the result of silencing of the FMR1 gene due to hypermethylation of the CGG expansion mutation, reactivation by targeted deoxyribonucleic acid (DNA) demethylation of the CGG expansion is a possible therapeutic strategy. Preliminary efforts in stem cells and even in postmitotic FXS neurons in vitro show encouraging data [52].

●Other strategies are exploring possible excision of the CGG expansion using the novel CrispR/Cas9 technology. Initial results, performed in induced pluripotent stem cells derived from patients with FXS, show that this is possible, albeit with low efficiency [53]. Another approach to excise the expansion involving the endogenous DNA repair machinery is under investigation [54]. The use of antisense oligonucleotides is also being explored as a possible therapeutic avenue [55].

HEALTH SUPERVISION — Children and adolescents with FXS should receive routine health supervision and prompt referral for medical, therapeutic, educational, and consultative services (eg, early intervention services, speech therapy) [2,7,56]. Health supervision guidelines from the American Academy of Pediatrics Committee on Genetics are available online.

Support — Families with fragile X mutation or premutation benefit from parental and social supports [7]. Personal and family support should be reviewed at regularly scheduled health supervision visits [6]. Internet-based information and support resources are provided below. (See 'Resources' below.)

Surveillance — In addition to intellectual disability and language and behavior problems, children and adolescents with FXS are at risk for a number of medical problems. Surveillance for these problems and appropriate intervention and/or referral should occur at regularly scheduled health maintenance visits throughout childhood, adolescence, and young adulthood [6].

Associated medical concerns in children and adolescents with FXS include [6,13,57]:

●Flat feet (80 percent) and other connective tissue manifestations (eg, ligamentous laxity, inguinal hernia) [57,58]. (See "Forefoot and midfoot pain in the active child or skeletally immature adolescent: Overview of causes", section on 'Flexible pes planus (flat feet)' and "Inguinal hernia in children".)

●Gastroesophageal reflux. (See "Gastroesophageal reflux in infants" and "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents".)

●Mitral valve prolapse (typically develops during adolescence or adulthood; present in 50 percent of adults) [57]. (See "Mitral valve prolapse: Clinical manifestations and diagnosis".)

●Recurrent otitis media (60 percent) [57,59]. (See "Acute otitis media in children: Epidemiology, microbiology, and complications" and "Acute otitis media in children: Clinical manifestations and diagnosis".)

●Macro-orchidism, hernias, and varicoceles. Macro-orchidism usually starts to develop at approximately nine years of age, and the testes size increases throughout puberty (mean testicular volume in adulthood: approximately 50 mL). Boys and adult males with a full mutation should be assessed for the presence of hernia or varicocele.

●Refractive errors (20 percent), strabismus (8 to 30 percent), and nystagmus [57]. (See "Refractive errors in children" and "Evaluation and management of strabismus in children", section on 'Evaluation'.)

●Seizures (as many as 20 percent) [60-62]. The peak incidence is between six months and four years of age [12,61,62]. The possibility of seizures should be considered in older children and adolescents if school performance is declining or when a disturbed sleep pattern occurs. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis".)

●Scoliosis (<20 percent) [57]. (See "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis" and "Adolescent idiopathic scoliosis: Management and prognosis".)

●Depression [13]. (See "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis" and "Overview of prevention and treatment for pediatric depression".)

●Anxiety [13]. (See "Anxiety disorders in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, and course" and "Pharmacotherapy for anxiety disorders in children and adolescents" and "Psychotherapy for anxiety disorders in children and adolescents".)

Anticipatory guidance — The American Academy of Pediatrics guidelines for health supervision of children with FXS suggest providing anticipatory guidance according to the following schedule [2]:

●Birth to one month – Infants in this age group generally are identified through prenatal testing because of a positive family history. Review support groups and available services. Discuss how and what to tell family members and friends [63]. Review the recurrence risk for subsequent pregnancies; discuss options for family planning, including prenatal and preimplantation genetic testing. Review the family history regarding evaluation of other family members at risk of having a premutation or full mutation, or refer for formal genetic counseling to address these issues.

●One month to one year – Discuss irritability and tantrums. Refer for early intervention services (in the United States).

●One to five years – Review the preschool program. Refer for speech and language therapy, physical therapy, and occupational therapy as indicated. Formal developmental evaluation may be warranted. There is no formal recommendation for when the developmental, educational (including speech and language), behavioral, and psychological assessments should take place. At the author's center, a complete assessment is performed at two and approximately four years of age.

●Five to 13 years – Assess effectiveness of behavioral interventions. Discuss how parents/caregivers and siblings address behavioral problems. Review development and appropriateness of school placement (eg, visual presentation of information, small classroom size, individualized attention, speech and language therapy, occupational therapy). (See 'Developmental and educational interventions' above and 'Behavioral interventions' above.)

●Thirteen to 21 years – Review behavioral concerns (eg, violent outbursts). Assess psychosocial development, physical and sexual development, and fertility. Discuss the need for and level of supervision, and discuss the need for birth control. The National Fragile X Foundation provides resources for discussing sexuality with children and adolescents with FXS. Discuss the need for vocational training and group home placement, if appropriate. Facilitate transition to adult medical care as appropriate or desired.

PRADER-WILLI PHENOTYPE — Treatment of children with the Prader-Willi phenotype of FXS is similar to that for children with Prader-Willi syndrome without FXS. (See "Prader-Willi syndrome: Management", section on 'Recombinant growth hormone treatment' and "Prader-Willi syndrome: Management", section on 'Feeding and obesity' and "Prader-Willi syndrome: Management".)

PROGNOSIS — Life expectancy for individuals with FXS is normal [7]. Adult males typically have an intelligence quotient (IQ) in the moderate intellectual disability range (the average IQ in adult males with a completely methylated full mutation is approximately 40) [3,64]. However, IQ may vary from mild to severe. Males with incomplete methylation of FMR1 may have IQ in the borderline or low-normal range. Adult females with the full mutation usually have IQ in the normal or mild intellectual disability range. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis".)

RESOURCES — Internet-based resources for health care providers, patients, and parents/caregivers of with FXS include [63]:

●The National Fragile X Foundation (includes a section on FXS resources by age group)

●FRAXA Research Foundation

●The National Institute of Child Health and Human Development

●Genetic Testing Registry (GTR)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fragile X syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Fragile X syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Management overview – The management of children and adolescents with fragile X syndrome (FXS) is individualized according to the child's cognitive and behavioral symptoms, as well as strengths and weaknesses. Interventions may include individualized education programs, speech and language therapy, occupational therapy, behavior therapy, and pharmacotherapy. (See 'Introduction' above.)

●Genetic counseling – Families of persons with FXS should be referred to a geneticist or genetic counselor for a detailed discussion of the inheritance of the fragile X messenger ribonucleoprotein 1 (FMR1) mutation and testing of other family members. (See 'Genetic counseling' above.)

●Multidisciplinary assessment – Following initial diagnosis of FXS, children and adolescents should undergo a multidisciplinary evaluation for educational planning, assessment of behavioral and emotional needs, and associated medical problems (eg, gastroesophageal reflux, hypotonia, joint laxity, mitral valve prolapse, seizures, strabismus, recurrent otitis media, scoliosis). (See 'Evaluation to determine extent of disease' above.)

●Development and education – Children and adolescents with FXS usually have special educational needs and should be referred for early developmental stimulation/early intervention and special educational programs. (See 'Developmental and educational interventions' above.)

●Neuropsychiatric management – Behavioral interventions may be effective in promoting coping skills and reducing problematic behaviors (eg, aggression, stereotypic behaviors, self-injury). Psychopharmacologic intervention is individualized according to symptoms (eg, inattention, hyperactivity, anxiety, mood instability) and must be closely monitored. (See 'Behavioral interventions' above and 'Pharmacotherapy' above.)

●Health supervision – Health supervision of children with FXS involves surveillance for a number of associated medical problems, including flat feet, hyperextensible joints, inguinal hernia, gastroesophageal reflux, mitral valve prolapse, recurrent otitis media, refractive errors, strabismus, nystagmus, seizures, scoliosis, depression, and anxiety. (See 'Surveillance' above.)