Practice Essentials
Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited intellectual disability and autism and is the second most common cause of genetically associated mental deficiencies, after trisomy 21. Conservative estimates are that fragile X syndrome affects approximately 1 in 2500-4000 males and 1 in 7000-8000 females. The prevalence of female carrier status has been estimated to be as high as 1 in 130-250 population; the prevalence of male carrier status is estimated to be 1 in 250-800 population. The criterion standard diagnostic test for fragile X syndrome involves molecular genetic techniques that detect the fragile X messenger ribonucleoprotein 1 (FMR1) gene. [1]
Signs and symptoms of fragile X syndrome
Patients with fragile X syndrome present with problems in the following areas [2] :
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Developmental
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Cognitive
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Neuropsychological
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Musculoskeletal
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Feeding
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Toilet training
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Sleep
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Recurrent medical conditions
Developmental features
These include the following:
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During infancy, developmental milestones may be delayed, especially gross motor development secondary to hypotonia
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After the first year of life, delays in speech and language are notable, and fine motor skills are impaired
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As the patient matures, perseveration and echolalia may dominate speech patterns
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Expressive language ability, short-term memory, and attempts at problem solving are significantly impaired
Cognitive features
These include the following:
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Intelligence quotient (IQ) frequently indicates mild-to-severe intellectual disability (20-70)
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Females and less-affected males may have IQs that approach 80
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IQ may be higher in childhood than in adulthood because of slowing mental development and difficulties with IQ test taking rather than loss of intellect
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IQ in patients with premutations can be normal or slightly decreased
Neuropsychological features
These include the following:
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Depression
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General and separation anxiety
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Oppositional defiant disorder
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Autisticlike behavior
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In almost all male patients, behavioral features similar to those of attention deficit-hyperactivity disorder (ADHD), including aggressive tendencies and attention deficits
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Seizure disorders (typically complex partial seizures with onset at age 6-24 months)
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As children, difficulty when routines are altered
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Features of obsessive-compulsive disorder, sensory integration disorder, or both
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Self-injurious behavior and significant tantrums
Musculoskeletal features
These include the following:
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Pes planus
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Pectus excavatum
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Joint laxity
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Scoliosis
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Joint dislocation
Feeding difficulties
These include the following:
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Reflux, vomiting, or both
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Rarely, failure to gain weight during infancy and childhood
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In a minority of patients, a Prader-Willi phenotype, which includes obesity due to severe hyperphagia
Sleep disturbance
This includes the following:
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Difficulty falling asleep
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Frequent awakening
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Loud snoring, with or without obstructive sleep apnea
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Recurrent nonspecific medical problems
Eyes, ears, and nose
Problems include the following:
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Otitis media
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Recurrent sinusitis
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Decreased visual acuity
The phenotype of fragile X syndrome is difficult to diagnose in prepubertal children. Most physical examination findings are notable only after onset of puberty. Physical findings are as follows:
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Growth: Childhood growth is marked by an early growth spurt, but adult height is often average or slightly below average. Additionally, obesity during adolescence and early adulthood is common.
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Statistically significant phenotypic characteristics of young males with fragile X syndrome include the presence of a hallucal crease (a single crease between the first and second toes), sensitivity to touch, and the inability to touch the tongue to the lips [3]
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A small subset of male patients may have obesity, poor linear growth, small hands and feet, and diffuse hyperpigmentation
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Craniofacial: Adolescent and adult patients have a long, thin face with prominent ears, prominent foreheads, facial asymmetry, a head circumference higher than the 50th percentile, and a prominent jaw
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The mouth has dental overcrowding and a high-arched palate
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Ears are typically large and may protrude
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Eyes: Strabismus is frequent; occasionally, nystagmus, astigmatism, and ptosis are present
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Hands and feet: hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus; clubfeet may be present at birth
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Pectus excavatum and scoliosis are frequent findings
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Genitals: Macroorchidism is nearly universal in postpubertal males
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During childhood, an increased incidence of inguinal hernias is reported
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Cardiac: A heart murmur or click consistent with mitral valve prolapse is often auscultated
See Clinical Presentation for more detail.
Diagnosis of fragile X syndrome
DNA testing for fragile X syndrome is recommended. Karyotyping may reveal other chromosomal anomalies, and both a standard karyotype and DNA testing are suggested when a possible diagnosis of fragile X syndrome is considered. The criterion standard diagnostic test involves molecular genetic techniques that detect the FMR1 gene. The exact number of CGG triplet repeats can be determined. Southern blot and polymerase chain reaction (PCR) are the 2 methods of genetic analysis that are currently available.
Features of Southern blot analysis are as follows:
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Provides a more accurate estimation of the number of CGG triplet repeats if a full mutation is present (with a large CGG expansion)
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Can also be used to evaluate the degree of methylation at the CGG repeat site
Features of PCR are as follows:
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Faster than Southern blot analysis
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Requires a minimal sample
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Less expensive than Southern blot analysis
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More accurately estimates the number of CGG triplet repeats if a premutation is present (with small-to-moderate increases in CGG repeats)
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PCR can be used to assess the number of AGG triplet repeats in female patients with a premutations; these AGG repeats interrupt the CGG repeats in some patients with premutations and are felt to stabilize the CGG repeats and prevent premutations in women from expanding into full mutations in their offspring; the presence and number of AGG repeats (which is directly proportional to the protection from conversion to full mutations) assist in the genetic counseling of women with premutations; therefore, greater than 2 AGG repeats is more protective than 0 or 1 AGG repeats [4]
See Workup for more detail.
Management of fragile X syndrome
Routine care involves treating the medical problems that these patients commonly experience, including gastroesophageal reflux, sinusitis, and otitis media. During infant and early childhood healthcare maintenance visits, focus examination on possible hip dislocations, hernias, and hypotonia.
Consultations may include the following:
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Genetic specialist: Genetic counseling to inform patients and families and to assist with family planning and reproductive decisions
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Speech and language therapist
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Occupational and physical therapist
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Behavioral intervention/modification team: Specific areas of focus include social eye contact and stress reduction training
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Special education professional: Consultation with a special education professional is appropriate to assess the level of cognitive functioning, ADHD symptoms, and aggressiveness and to initiate sensory integration therapy for behavior problems
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Psychology or behavioral specialist: To assist families with methods for decreasing negative behavior; additionally, some patients benefit from social skills–oriented therapy and individual counseling
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Neurologist: Consult a neurologist if seizures persist
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Cardiologist
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Otolaryngologist: Patients with chronic sinusitis and chronic otitis media require an evaluation by an otolaryngologist
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Ophthalmologist: Important for patients with strabismus
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Gastroenterologist
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Orthopedic surgeon: Assesses patients for abnormal gait caused by pes planus, which is managed with orthotic inserts or orthopedic shoes, and may provide surgical intervention for severe scoliosis
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Nutritionist: For patients with the Prader-Willi syndrome phenotype
See Treatment and Medication for more detail.
Background
Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited intellectual disability and autism and is the second most common cause of genetically associated mental deficiencies after trisomy 21. In 1943, Martin and Bell investigated a family with multiple male members who had intellectual disability. [5] They were able to link the cognitive disorders to an unidentified mode of X-linked inheritance. In 1969, Lubs discovered excessive genetic material that extended beyond the long arm of the X chromosome in affected males and in their unaffected female relatives. [6] These results were impossible to reproduce until the importance of the folate-deficient thymidine-deficient medium, which was used in the initial studies to culture lymphocytes, was realized.
Since the 1960s and early 1970s, progress toward mapping the gene has been steady and rewarding, and the precise genetic defect that causes fragile X syndrome has been characterized. Advances in molecular genetics have provided reliable diagnostic testing. Clinically, patients with fragile X syndrome have an array of physical, cognitive, and neurobehavioral features.
Overview of special concerns
Because fragile X syndrome is underdiagnosed, has a high prevalence, and is inheritable, preconceptual and antenatal molecular genetic screening is encouraged for women.
Obstetricians and primary care providers should recommend screening in high-risk cases. Additionally, a geneticist, genetic counselor, or both should be available to provide accurate information to families if screening findings are positive for fragile X mutations.
Southern blot analysis, polymerase chain reaction (PCR), and immunocytochemical testing are used for diagnosing maternal, preimplantation, and fetal premutations; full mutations; and associated proteins.
Fetal testing involving chorion villus sampling or amniocentesis may be performed and incurs the risks inherent to these procedures.
It is advisable to recommend prepregnancy or prenatal fragile X syndrome screening to women with a family history of fragile X syndrome or intellectual disability and to women with learning difficulties, intellectual disability, or both. All women who are known carriers of the premutation or full mutation should be offered prenatal testing.
In females with premutations, use of PCR testing to assess the number of AGG repeats that exist within the CGG repeats can assist in prepregnancy counseling. [4] Two or more AGG repeats within the CGG repeats appear to stabilize the premutation and decrease the likelihood that a mother will pass a full mutation to her offspring. [4]
Genetic counseling is important for women who have premutations and full mutations or who are carrying an affected child.
Fragile X syndrome testing should be considered for women with premature ovarian failure, for older adults with ataxia or tremor that could be associated with fragile X–associated tremor/ataxia syndrome (FXTAS), and in children with autism, autism-spectrum disorder, or intellectual disability. Girls with deletions or mutations of the FMR1 gene having severe/refractory epilepsy and significant neourodevelopmental delays have been reported. Some experts recommend molecular testing for all males and females with developmental concerns and epilepsy. [7]
Some states are considering adding fragile X syndrome to their newborn screening programs.
Public awareness about fragile X syndrome is increasing thanks to media attention, including an article in Time Magazine on June 26, 2008.
Pathophysiology
Cognitive, behavioral, and neuropsychological difficulties characterize the syndrome. [2] These signs are especially important in alerting physicians, parents, and teachers to deficits exhibited by preschool-aged children and elementary school–aged children. This group represents the age at which the diagnosis of fragile X syndrome is often made or considered.
Problems include mild-to-moderate autisticlike behavior (most notably, hand flapping and avoidance of eye contact), shyness, sensory integration difficulties, attention deficits, hyperactivity, impulsivity, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), depressed affect, anxiety, intellectual disablity (intelligence quotient [IQ] is typically 35-70), mathematical learning disabilities, [8, 9] aggressive tendencies, deficiency in abstract thinking, developmental delays after reaching early milestones (especially speech and language delays), and decreasing IQ with increasing age.
The wide range of these abnormalities is partially related to each individual's environment, maternal psychopathology, and available educational and therapeutic opportunities, especially in affected males. Patients with high-functioning home environments and appropriate education services demonstrate higher IQs and improved behavioral outcomes.
A prospective study by Del Hoyo Soriano et al indicated that in patients with fragile X syndrome, a higher level of fragile X messenger ribonucleoprotein (FMRP) and a lower ratio of affected-to-total chromosomes are associated with better gains in fluid intelligence (but not in crystallized intelligence). The evidence also indicated that the affected-to-total chromosome ratio is related to anxiety and social withdrawal levels. [10]
In addition, physical signs are associated with fragile X syndrome; however, these signs are more obvious during adolescence or after puberty and rarely result in disabilities. In addition to the cognitive, behavioral, and neuropsychological findings, the organ systems most frequently involved include the craniofacial, genital, and musculoskeletal systems.
Fragile X-associated tremor ataxia syndrome (FXTAS) has been reported in 33-46% of men older than 50 years and, less frequently (4-8%), in older women with premutations in the FMR1 gene. Full mutations of this gene result in fragile X syndrome. Clinical features of FXTAS include incontinence, impotence, cerebellar ataxia, peripheral neuropathy, autonomic dysfunction/orthostatic hypotension, severe intention tremor, and other signs of neurodegeneration, such as brain atrophy, memory loss and dementia, anxiety, depression, and irritability. Premature ovarian failure is reported in 25% of women with premutations; this represents a 30-fold increase compared with the general population.
The risk of fragile X–associated primary ovarian insufficiency is directly related to the number of CGG repeats. Symptoms include irregular menses, decreased fertility, premature ovarian failure, and laboratory abnormalities, such as elevated follicle-stimulating hormone (FSH) levels. Studies attempting to develop a predictive model for the timing of premature ovarian failure are underway and include the number of CGG repeats, environmental effects, and genetic factors. [11] Associations between women with premutations and autoimmune diseases (hypothyroidism and fibromyalgia) have been reported. In women with a diagnosis of ovarian insufficiency, 2-15% have a premutation. [12]
Frequency
United States
Conservative estimates report that fragile X syndrome affects approximately 1 in 2500-4000 males and 1 in 7000-8000 females. The prevalence of female carrier status has been estimated to be as high as 1 in 130-250 population; the prevalence of male carrier status is estimated to be 1 in 250-800 population. As many as 10% of cases of previously undiagnosed intellectual disability in males and 3% of cases of previously undiagnosed intellectual disability in females are attributed to fragile X syndrome.
International
Exact frequency is unknown. However, data collected from England and Australia are comparable to data from the United States.
Mortality/Morbidity
Aside from the morbidity associated with intellectual disability and cognitive, behavioral, and neuropsychological problems, the morbidity and mortality associated with fragile X syndrome are unremarkable. Life span is generally unaffected by the disorder.
Race
Fragile X syndrome has been described in all racial and ethnic groups. The overall frequency in other countries is slightly lower than in the United States. Whether this is related to racial or ethnic diversity or to diagnostic technology is unclear.
Sex
Females carry the gene abnormality 2-4 times more often than males; however, only about one third of females who carry the abnormal gene demonstrate decreased intelligence. Females with the disorder are more likely to have less impairment and less obvious physical characteristics. Males with the disorder are more likely to be sensitive to environmental factors.
The pattern of inheritance most closely resembles X-linked dominance with variable penetrance. Occasionally, females are severely affected because of the complex genetics of the disorder.
Age
Fragile X syndrome is an inherited disorder and is present at birth.
If the intellectual disability is discovered during a prenatal or family history, diagnosis is typically made at a younger age. If the physician is intimately acquainted with the patient’s family, providers may be alerted to possible maternal carrier states in mothers who display cognitive impairment. Therefore, developmental delays in children are appreciated earlier.
As patients complete puberty, the characteristic craniofacial features, in addition to the cognitive, behavioral, and neuropsychological disabilities, alert physicians to the possibility of a genetic disorder.
Despite provider education and fragile X syndrome advocates, the average age of diagnosis for males (35-37 mo) and fully-mutated females (41 mo) remained unchanged between 2001 and 2007. [13]
