Fragile X syndrome: Clinical features and diagnosis in children and adolescents

INTRODUCTION — Fragile X syndrome (FXS) is an X-linked disorder and the most common inherited cause of intellectual disability [1]. Both males and females can be affected.

The clinical features and diagnosis of FXS in children and adolescents are discussed in this topic review. Prenatal screening and the management of FXS in children and adolescents are discussed separately. (See "Prenatal screening and diagnosis for fragile X syndrome" and "Fragile X syndrome: Management in children and adolescents".)

PATHOGENESIS — FXS is an X-linked disorder. It is caused by a loss-of-function variant in the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at Xq27.3 that results in decreased or absent levels of fragile X messenger ribonucleoprotein (FMRP) [2,3]. In more than 99 percent of cases, loss of function is caused by an unstable expansion of a trinucleotide (cytosine-guanine-guanine [CGG]) repeat at the 5' untranslated region of the gene [4,5]. Deletions, point mutations, and missense mutations in FMR1 also may cause FXS but are very rare [4,6,7].

There are two clinically significant levels of CGG expansion:

●Full mutation – Expansion of >200 repeats is known as full mutation and leads to methylation-coupled silencing of the FMR1 gene and absence of FMRP, causing the classical FXS phenotype. (See 'Full mutation in males' below and 'Full mutation in females' below.)

●Premutation – A smaller expansion of between approximately 50 to 55 and 200 repeats is known as premutation. The FMR1 gene remains transcriptionally active, FMRP is produced, and the classic FXS phenotype does not occur. However, a spectrum of clinical findings is associated with the premutation. Premutation alleles exhibit instability upon transmission, especially from a carrier mother, and may result in a full mutation in one or more generations [8-11]. (See 'Premutation' below.)

DNA methylation turns off gene activity, thus preventing gene transcription. Elongation of the CGG repeats allows hypermethylation of FMR1, resulting in impaired transcription and reduced production of the FMRP. Lower levels of FMRP appear to have a major impact upon the severity of the FXS phenotype. Individuals with nearly normal levels of FMRP may have mild or no symptoms, while those with very little or no normal FMRP may have more severe symptoms. (See "Principles of epigenetics", section on 'DNA methylation'.)

The genetics and molecular biology of FXS are discussed in detail separately [12]. (See "Prenatal screening and diagnosis for fragile X syndrome", section on 'Overview'.)

EPIDEMIOLOGY — FXS (MIM #300624) is the most frequent form of inherited intellectual disability, with a disease prevalence due to the full mutation of between 1 in 4000 and 1 in 7000 in males [1,4,13]. The prevalence of the full mutation in females, which has a variable clinical presentation, is approximately two-thirds to one-half of that in males [4,13]. However, this prevalence measure may be inappropriately low as females with a mild phenotype may go undiagnosed. The premutation rate is approximately 1 in 750 to 1 in 850 men and 1 in 250 to 1 in 300 in women [1,13-15]. FXS has been diagnosed in up to 3 percent of males with significant neurodevelopmental disorders (eg, autism, nonsyndromic intellectual disability) [16].

CLINICAL FEATURES — The clinical features of FXS vary depending upon the mutation state (full mutation versus premutation), degree of methylation, sex, tissue variation/mosaicism, and possibly magnitude of the fragile X messenger ribonucleoprotein (FMRP) deficit (table 1) [4,5,16-19]. Males with the full mutation are usually significantly affected. The degree of impairment varies widely in females with the full mutation.

Full mutation in males — All males with the full mutation have manifestations of FXS, but there is a wide range of physical, cognitive, and behavioral features [20]. The physical features may be subtle. The classic presentation is a young male with global developmental delay and typical behavioral characteristics, described below. Males with FXS are at variable risk for autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) [21,22]. (See 'Cognitive function' below and 'Behavioral features' below and 'Autism' below.)

Physical features — The physical features of FXS in males vary depending upon age [16,23-27].

●Adolescents - The classic physical manifestations are more obvious in adolescents (picture 1):

•Long and narrow face with prominent forehead and chin (prognathism)

•Large ears

•Testicular enlargement (volume >25 mL after puberty) with normal testicular function

●Infants and children – Physical manifestations are subtle in infants and children. Nonetheless, some craniofacial and connective tissue findings may be present from a young age (picture 2). These include [16,20,25,28-30]:

•Relative macrocephaly (head circumference >50^th percentile for age and sex) [4]

•Strabismus

•Pale blue irises

•Midface hypoplasia with sunken eyes

•Arched palate

•Mitral valve prolapse (seemingly benign)

•Joint hyperlaxity (particularly of the thumbs, fingers, and wrists)

•Hypotonia

•Doughy skin over the dorsum of hands

•Flexible flat feet

Testicular enlargement is usually not seen in males under eight years of age [24,31].

Macrocephaly is related to underlying structural anomalies. Magnetic resonance imaging and quantitative morphometry demonstrate that individuals with an FMR1 gene full mutation have increased total brain volume, with relatively increased caudate nucleus, fourth ventricle, and hippocampal volumes and decreased cerebellar vermis volume [32-34]. In addition, males with FXS have decreased lateral ventricle volume [32]. Caudate nucleus volume correlates with the methylation status of the FMR1 gene, and both caudate nucleus and lateral ventricular volumes correlate with intelligence quotient (IQ).

Cognitive function — Developmental delay (including delayed attainment of motor and language milestones), intellectual disability, and learning disabilities are the most salient clinical features of FXS [35]. In addition, cognitive level and adaptive behavior skills decline after early childhood, reflecting the slow acquisition of skills compared with other children of the same age rather than a regression of skills [20,36-40]. The decline occurs in all areas: quantitative skills, verbal reasoning, visual/abstract abilities, and short-term memory [38]. These observations highlight the importance of early intervention to facilitate cognitive abilities and adaptive behavior skills [20,39]. FXS is unlikely in the child with normal intelligence. (See 'Diagnosis' below and "Fragile X syndrome: Management in children and adolescents".)

Males with FXS typically sit alone at 10 months, walk at 20.6 months, and say their first clear words at 20 months (compared with approximately 7 months, 13 months, and 11 months, respectively, in typically developing children) [4].

Males with FXS have delayed language development. Expressive language skills are achieved more slowly than receptive language skills, and the discrepancy between expressive and receptive skills increases with age [35,41]. Approximately 10 percent of males with FXS are nonverbal [42].

Expressive language is often tangential (eg, responses or comments that do not relate to the topic of conversation) and perseverative, with inappropriate self-repetition, echolalia (involuntary parrot-like repetition), and pragmatic errors [20,35,43].

Articulation is poor, and language is repetitive and characterized by short and fast utterances [44]. Cluttering is often present. Cluttering is a rapid, fluctuating rate of speech with repetitions of sounds, words, and phrases and occasional garbled, slurred, or disorganized speech.

Prepubertal males with FXS, particularly preschoolers, generally have higher IQs than adolescents and adults with FXS [44]. Adult males typically have an IQ in the moderate intellectual disability range, but intellectual disability ranges from mild to severe. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis", section on 'Severity classification'.)

Although individual strengths and weaknesses may vary from patient to patient, common strengths among males with FXS include verbal skills (verbal reasoning, simple labeling, vocabulary, verbal comprehension) [20]. Common weaknesses include mathematics abilities, visuospatial abilities, attention and executive function (eg, the ability to organize information, plan ahead, problem solve), and visual-motor coordination [20,36,45-47].

Behavioral features — Males with FXS often have neurobehavioral disabilities, including ADHD, anxiety, and ASD [22,36,48-51]. Clinical features include hyperactivity, inattention, gaze aversion, and stereotypic movements, such as hand flapping, hyperarousal, social anxiety, unusual speech patterns. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Restricted and repetitive behavior, interests, and activities' and 'Autism' below and "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Core symptoms' and "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features'.)

Males with FXS tend to be more inattentive, overactive, and impulsive than males with other types of intellectual disability [48]. These symptoms may be related to sensory hyperreactivity and lack of stimulus inhibition and may lead to a diagnosis of ADHD. These symptoms tend to decline with age, but many adult males with FXS remain hyperactive. Treatment with stimulant medication may be beneficial [5]. (See "Fragile X syndrome: Management in children and adolescents", section on 'Hyperactivity and inattention'.)

Males with FXS may have avoidant behaviors, particularly when their intellectual disability is severe [49]. They tend to avoid new situations and to move away from new objects [48]. However, they do not remain socially withdrawn, unless they have ASD, or avoid familiar people.

Males with FXS also may have anxiety symptoms (nervousness, obsessive-compulsive disorder-like obsessions), mood instability, aggressive behavior, and self-injurious behavior [52-54].

Autism — It is estimated that 18 to 67 percent of males with FXS meet the criteria for ASD [49,55,56]. Males with FXS and autism have greater impairments in cognitive skills, social interaction, academic achievement, language ability, and adaptive behavior than males with FXS alone and are also more likely to have seizures [5,57-60]. (See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis", section on 'Evaluation for associated conditions' and "Autism spectrum disorder in children and adolescents: Clinical features".)

Seizures — Approximately 10 to 20 percent of males with FXS develop seizures [61-63]. The risk of seizures is highest in childhood (peak incidence between six months and four years; mean age of onset two years) [5,62,63]. Most are simple or complex partial seizures, including benign childhood epilepsy with centrotemporal spikes (also known as benign rolandic epilepsy), although other types can occur. The seizures are relatively easy to control and often spontaneously remit during childhood [5]. (See "Benign (self-limited) focal epilepsies of childhood", section on 'Benign epilepsy with centrotemporal spikes' and "Fragile X syndrome: Management in children and adolescents", section on 'Seizures'.)

Additional associated findings — Children with FXS can have slow motor development and often present with hypotonia in infancy. Infants with hypotonia can have associated feeding problems, gastroesophageal reflux, and recurrent otitis. (See "Fragile X syndrome: Management in children and adolescents", section on 'Evaluation to determine extent of disease'.)

Strabismus, joint laxity, and mitral valve prolapse may also be present. Except for strabismus, these findings usually do not demand surgical intervention.

Prader-Willi phenotype — A subgroup of males with FXS has a phenotype similar to that of Prader-Willi syndrome (PWS; ie, obesity and hyperphagia) but do not have the characteristic cytogenetic or methylation abnormalities at 15q11-13 [64-67]. Autism is more common in males with FXS and the Prader-Willi phenotype than in males with FXS without the Prader-Willi phenotype (54 versus approximately 30 percent) [67]. (See "Prader-Willi syndrome: Management" and "Prader-Willi syndrome: Clinical features and diagnosis" and 'Autism' above.)

Full mutation in females — The phenotype of full-mutation FXS in females is much more variable than in males because of individual differences in inactivation of the fragile X chromosome [20]. Approximately 50 percent of females with a full fragile X mutation have normal intellect. The remaining 50 percent usually have milder features than males, but the full spectrum of cognitive, behavioral, and physical findings may occur [16].

As many as 50 percent of females with the full mutation have some of the characteristic physical features (eg, prominent ears) [68]. Approximately 50 percent of women with the full mutation have Iqs in the borderline or mild intellectual disability range [68-71]. Cognitive impairment appears to correlate with the activation ratio of the fragile X chromosome rather than the size of the amplification [72]. As in males with full-mutation FXS, cognitive function may decline after early childhood. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis".)

Many females with the full mutation have associated behavioral or emotional problems [52,68,73]. They typically present with learning difficulties (especially in math), attention problems (or ADHD), shyness, social anxiety, or selective mutism [42]. Deficits in visual-motor coordination, executive function (eg, the ability to organize information, plan ahead, problem solve), and language are common [42,74-76]. Females with the full mutation are at risk for affective and schizophrenia spectrum disorders [52,77]. Autistic behaviors (eg, communication and social interaction deficits, stereotypies) are more commonly reported among 6- to 16-year-old females with FXS than age- and IQ-matched controls [78]. Approximately 20 percent of females with FXS meet the criteria for ASD [49,55,56]. (See "Specific learning disorders in children: Clinical features", section on 'Clinical features' and "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Core symptoms' and "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features' and "Autism spectrum disorder in children and adolescents: Clinical features".)

Approximately 5 percent of females with FXS develop seizures [61-63]. (See 'Seizures' above.)

Premutation — Individuals with fragile X premutation have between 55 and 200 cytosine-guanine-guanine (CGG) repeats. At this level, the FMR1 gene remains transcriptionally active, and the classic FXS phenotype does not occur. (See 'Pathogenesis' above.)

There are three potential areas of concern for individuals with fragile X premutations:

●Premature ovarian insufficiency (POI) in women, which is discussed separately (see "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)")

●Fragile X-associated tremor-ataxia syndrome (FXTAS) later in life, which is discussed separately (see "Autosomal dominant spinocerebellar ataxias", section on 'Fragile X-associated tremor/ataxia syndrome')

●Neurocognitive deficits [79]

In the past, fragile X premutation was not thought to affect cognitive function. However, there are reports of individuals with premutation and neurobehavioral manifestations, including cognitive and social skills deficits, anxiety, executive dysfunction, and autism [5,80-83]. Decreased FMRP levels have been detected in some of these individuals, suggesting a spectrum of clinical severity related to relative FMRP deficit [80,84].

The author's clinical practice has identified several males with fragile X premutation and learning problems, developmental delay, or autistic features. This may reflect an ascertainment bias. However, they have identified four times more premutations in males younger than 16 years with developmental problems who were referred for FMR1 gene testing than would be expected based upon the known prevalence of the premutation in males (unpublished data). Larger and more longitudinal studies are necessary, but these data provide additional evidence that fragile X premutations may affect neurocognitive and behavioral functioning in children.

DIAGNOSIS — It is important to make the diagnosis of FXS as early as possible so that appropriate interventions (eg, speech and language therapy, special education support, genetic counseling) can be initiated [42]. Surveys of parents of children diagnosed with FXS indicate a significant delay between the onset of their concerns (average age approximately 12 months) and the diagnosis of FXS (average age 35 to 37 months). Approximately one-fourth of families had a second child with a full mutation before the first child was diagnosed [85,86]. The diagnosis is based upon the phenotypic presentation as well as the genotype.

Indications for testing — In the absence of a family history of FXS, the diagnosis of FXS requires clinical suspicion based upon cognitive, developmental, or behavioral concerns, as described above. The diagnosis is confirmed by molecular testing. (See 'Clinical features' above and 'FMR1 DNA analysis' below.)

Child with suspected FXS — The American Academy of Pediatrics Committee on Genetics recommends genetic testing for FXS (see 'FMR1 DNA analysis' below) in children with any of the following, particularly when associated with physical and behavioral characteristics of FXS or a relative with undiagnosed intellectual disability [87]:

●Developmental delay

●Borderline intellectual abilities or intellectual disability

●Diagnosis of autism without a specific etiology

Although the yield of molecular testing in such individuals is low [88], early diagnosis is important for timely genetic counseling. (See "Prenatal screening and diagnosis for fragile X syndrome", section on 'Candidates for screening' and "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis", section on 'Genetic testing' and "Intellectual disability in children: Evaluation for a cause", section on 'Testing for fragile X syndrome'.)

Adult with suspected FXS — Genetic testing should also be offered to the following patients, after an appropriate explanation of the test and its potential implications for the patient and their family [87]:

●Females with primary ovarian insufficiency (POI)

●Patients over 50 years of age with progressive cerebellar ataxia and intention tremor

●Adults with typical physical features and intellectual disability without a specific etiology

Testing for mutations in the FMR1 gene is also suggested for persons who had cytogenetic testing in the past if the results of the testing and the clinical/behavioral phenotype are inconsistent [89].

FXS suspected due to family history — Family history findings that are suggestive of FXS include [16]:

●Cognitive effects – Intellectual disability, developmental delay, learning disabilities, specific problems with mathematics

●Speech delay or unusual speech pattern

●Autism spectrum disorder (ASD) or autistic-like behaviors

●Attention deficit or attention deficit hyperactivity disorder (ADD/ADHD)

●Dysmorphic features – Macrocephaly, large ears, long face, broad forehead, prominent jaw, strabismus, large testicles

●Features of loose connective tissue – Hyperextensible joints, flat feet, hypotonia, mitral valve prolapse, hernias

●Neurologic symptoms – Seizures, late-onset progressive tremor, ataxia, difficulty walking, balance problems, short-term memory loss, loss of sensation in limbs

●Mental illness/personality disorders – Depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder, schizoaffective disorder, schizoid personality

●Behavioral problems – Impulsiveness, anger outbursts, violent behavior, solitary behavior, counseling or medication for behavioral difficulties

●Shyness, social anxiety, excessive worrying, counseling or medication for emotional difficulties

●Premature menopause, fertility problems

Molecular testing is warranted if several of these family history features are present in combination in a symptomatic person (eg, a child with developmental delay and/or behavioral problems, a woman with premature menopause, or an older male with ataxia) or in someone with a strong family history. Genetic counseling and genetic testing are also suggested for at-risk family members of patients with FXS, even if they are asymptomatic.

FMR1 DNA analysis — The diagnosis of FXS is based upon detection of an alteration in the FMR1 gene [4]. Measuring the number of repeats in the CGG segment of FMR1 is used to identify persons with premutation or full mutation, in addition to those who have a normal or intermediate number of repeats. Testing methods and indications for prenatal screening are discussed separately. In addition, a detailed description of molecular genetic tests and the testing strategy for FMR1-related disorders is available through the Genetic Testing Registry (GTR). (See "Prenatal screening and diagnosis for fragile X syndrome", section on 'Preconception and prenatal screening' and "Prenatal screening and diagnosis for fragile X syndrome", section on 'Laboratory testing'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of FXS includes other causes of intellectual disability or developmental delay, including [4,90,91] (see "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis"):

●Fragile XE syndrome (FRAXE) – FRAXE, which is extremely rare, is characterized by mild intellectual disability without consistent physical features. It has been described in males with expanded cytosine-cytosine-guanine (CCG) repeats in AF4/FMR2 family member 2 (AFF2) gene, near the FMR1 gene.

●XXY (Klinefelter syndrome) – Males with Klinefelter syndrome may have specific learning disabilities, particularly in expressive language. In contrast to postpubertal males with FXS, males with XXY usually have small testes. (See "The child with tall stature and/or abnormally rapid growth", section on 'Klinefelter syndrome'.)

●Cerebral gigantism (Sotos syndrome) – Characteristic features of cerebral gigantism include typical facial appearance (macrocephaly, frontal bossing, prominent chin, pointed chin, downslanting palpebral fissures), overgrowth, learning disability, behavioral problems, and congenital cardiac anomalies. (See "The child with tall stature and/or abnormally rapid growth", section on 'Cerebral gigantism'.)

●Prader-Willi syndrome (PWS) – Some males with FXS have a phenotype similar to that of PWS, but they do not have the genetic abnormalities associated with PWS. (See "Prader-Willi syndrome: Management" and 'Prader-Willi phenotype' above.)

RESOURCES — FXS resources for health care providers, parents/caregivers, and patients include:

●The National Fragile X Foundation

●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

●Epidemiology – Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability, with a prevalence between 1 in 4000 and 1 in 7000 in males. The prevalence in females is approximately two-thirds to one-half of that in males. (See 'Epidemiology' above.)

●Genetics/pathogenesis – FXS is an X-linked disorder. It is caused by a loss-of-function mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene that leads to decreased or absent fragile X messenger ribonucleoprotein (FMRP). (See 'Pathogenesis' above.)

●Clinical features – The clinical features of FXS vary depending upon the mutation state (full mutation versus premutation), degree of methylation, sex, and tissue variation (table 1). (See 'Clinical features' above.)

•Males with full mutation – All males with full-mutation FXS have manifestations of FXS, but there are a wide range of physical, cognitive, and behavioral features. (See 'Full mutation in males' above.)

-Classic physical features include long and narrow face with prominent forehead and chin, large ears, and testicular enlargement, but these features typically are not obvious until adolescence or adulthood (picture 1). Physical features in younger males may include macrocephaly, strabismus, midface hypoplasia, arched palate, mitral valve prolapse, hyperextensible joints, hypotonia, soft skin, and flexible, flat feet.

-Intellectual disability is usually in the moderate range. Expressive language is more affected than receptive language.

-Behavioral features may include features of attention deficit hyperactivity disorder (ADHD; hyperactivity, inattention), autism spectrum disorder (ASD; gaze aversion, stereotypic movements [eg, hand flapping, hand biting], hyperarousal, social impairment, and unusual speech), or anxiety.

•Females with full mutation – Females with the full mutation usually have milder features than males, and 50 percent have normal cognitive function. However, the full spectrum of cognitive, behavioral, and physical findings may occur. (See 'Full mutation in females' above.)

●Diagnosis – In the absence of a family history of FXS, diagnosis of FXS requires a low threshold for clinical suspicion based upon cognitive, developmental, or behavioral concerns, as described above. Diagnosis is confirmed by molecular testing. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of FXS includes other causes of intellectual disability or developmental delay. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Carolyn Bridgemohan, MD (deceased), who contributed to an earlier version of this topic review.