Significant family, developmental, cognitive, and neuropsychological histories are keys to diagnosis. Unusual musculoskeletal anomalies, feeding difficulties, sleep disturbances (eg, difficulty falling asleep, frequent awakening, loud snoring with/without obstructive sleep apnea), and recurrent nonspecific medical problems are infrequently reported.
Screening and diagnosis in utero or during infancy is usually the result of a family history that features multiple male relatives with mental retardation.
Other clues to the diagnosis include a mother with learning disabilities, mental retardation, or both or family members with ataxia and tremors.
Female infertility secondary to premature ovarian failure and increased rates of dizygotic twinning have been discovered to be more common in fragile X carriers and may provide another clue to the diagnosis.
During infancy, developmental milestones may be delayed, especially gross motor development secondary to hypotonia.
After the first year of life, delays in speech and language are notable, and fine motor skills are impaired.
As the patient matures, perseveration and echolalia may dominate speech patterns. Expressive language ability, short-term memory, and attempts at problem solving are significantly impaired.
Intelligence quotient (IQ) frequently indicates mild-to-severe mental retardation (20-70). Females and less-affected males may have IQs that approach 80.
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.
IQ in patients with premutations can be normal or slightly decreased.
Patients have many neuropsychological features, including depression, general and separation anxiety, and oppositional defiant disorder.
Autisticlike behavior (especially poor eye contact, social avoidance, and hand biting/hand flapping) is present in 16-30% of patients with fragile X syndrome. However, some patients with autisticlike behavior may have social conversation abilities. Autism is diagnosed in 20% of females and 30% of males with fragile X syndrome; furthermore, an additional 30% of patients with fragile X syndrome are diagnosed with autism spectrum disorder. Molecular investigation for fragile X syndrome is the single laboratory test proven to aid in definitively diagnosing infantile autism.
Near-universal behavioral features of males with fragile X syndrome are similar to those observed in patients with attention deficit hyperactivity disorder (ADHD), including aggressive tendencies and attention deficits.
Approximately 20% of male patients and 5% of female patients have a seizure disorder, with nearly one half of those having persistent seizures that require anticonvulsant therapy. The onset of seizures is typically at age 6-24 months. The seizure type most often diagnosed is complex partial seizure. Additionally, simple febrile partial seizures and generalized tonic-clonic seizures may be present.
Many children have difficulty when routines are altered.
Some people with fragile X syndrome display features of obsessive-compulsive disorder, sensory integration disorder, or both. Others display self-injurious behavior and significant tantrums. Anxiety disorder is common.
Features include pes planus, pectus excavatum, joint laxity, scoliosis, and joint dislocation.
Affected individuals may manifest symptoms of reflux, vomiting, or both and, rarely, failure to gain weight during infancy and childhood. A minority of patients with fragile X syndrome demonstrate a Prader-Willi phenotype, which includes obesity due to severe hyperphagia.
Patients typically have delayed toilet training and frequent enuresis after toilet training.
Recurrent nonspecific medical problems
During the history taking, ask about apnea. 
The phenotype of fragile X syndrome is difficult to diagnose in prepubertal children. Most physical examination findings are notable only after onset of puberty.
Childhood growth is marked by an early growth spurt. However, adult height is often average or slightly below average. Additionally, obesity during adolescence and early adulthood is common.
A study by Lachiewicz et al reported 3 statistically significant phenotypic characteristics of young males with fragile X syndrome compared with young males with other developmental delays.  These characteristics included 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.
A small subset of male patients were reported with obesity, poor linear growth, small hands and feet, and diffuse hyperpimentation.
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.
The mouth has dental overcrowding and a high-arched palate.
Ears are typically large and may protrude.
Strabismus is frequently noted. Occasionally, nystagmus, astigmatism, and ptosis are present.
Hands and feet manifest nonspecific findings, including hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus. Clubfeet may be present at birth.
Back and chest
Pectus excavatum and scoliosis are frequent findings.
Macroorchidism is nearly universal in postpubertal males. In unaffected males, average testicular volume is 17 mL; in patients with fragile X syndrome, testicular volume is more than 25 mL and can be as high as 120 mL. During childhood, an increased incidence of inguinal hernias is reported.
A heart murmur or click consistent with mitral valve prolapse is often auscultated and requires consultation with a cardiologist.
The genetic defect is dynamic and lies at the distal end of the long arm of the X chromosome. Careful examination of the karyotype of affected individuals' lymphocytes, cultured in a folate-depleted and thymidine-depleted medium, reveals a constriction followed by a thin strand of genetic material that extends beyond the long arm at the highly conserved band Xq27.3. This constriction and thin strand produce the appearance of a fragile portion of the X chromosome, leading to the term fragile X.
The function of the band Xq27.3, which is also termed the fragile X mental retardation-1 (FMR1) gene, is to synthesize fragile X mental retardation protein (FMRP), a regulatory protein that binds messenger RNA (mRNA) in neurons and dendrites.  In patients with a full mutation in the FMR1 gene, FMRP is not manufactured because of hypermethylation of FMR1, and brain development is impaired primarily because of abnormal synapse connections. Additionally, mutations in the FMR1 gene lead to excessive activity of the metabotropic glutamate receptor 5 (mGluR5), which results in many fragile X syndrome symptoms. FMRP is present in other tissues; however, its role is less understood.
Once identified and sequenced, the gene was discovered to contain a repeating base pair triplet (CGG) expansion, which is responsible for fragile X syndrome.
Unaffected individuals have 5-54 CGG repeats in the first exon at the 5' end of band Xq27.3. Individuals with 45-54 repeats are unaffected, but they risk passing a premutation on to future generations. A span of 55-199 repeats is known as a premutation, whereas 200 or more repeats is a full mutation. Full mutation results in hypermethylation of the cysteine bases and restricts protein binding, leading to gene inactivation and absent FMRP. Mosaic patterns are common. The number of repeats is unstable from generation to generation, making the pattern of inheritance difficult to predict. In addition, the degree of methylation is directly proportional to the signs and symptoms of fragile X syndrome.
Males with a full mutation have fragile X syndrome. Mothers of nearly all males with fragile X syndrome have premutation or fragile X syndrome. Males with fragile X syndrome pass a premutation to their daughters because sperm cells are mosaics. Sons are unaffected because they receive the Y chromosome from their fathers.
Half of females with the full mutation on a single X chromosome are unaffected because of inactivation of the other X chromosome. The other half of females have fragile X syndrome, although with less severe mental retardation than males with the disorder. These affected females can pass the gene to their children.
Males with a premutation are usually unaffected to mildly affected and transmit the premutation to their daughters. The mutation is stable; thus, the CGG triplets are not increased. Sons of affected males are unaffected because they receive the Y chromosome from their fathers.
Females with a premutation are usually unaffected to mildly affected with fragile X syndrome. However, they have a 20% chance of having fragile X – associated primary ovarian insufficiency. Unlike their male counterparts, the CGG triplets are unstable and increase in size during oogenesis. If the number of repeats exceeds 200 and the oocyte is fertilized, a male child will have fragile X syndrome, and a female child will have a 50% chance of having fragile X syndrome. The number of repeats is directly proportional to the risk of the disorder in an offspring.
Although most patients with fragile X syndrome have a CGG triplet expansion, few patients have a point mutation in the FMR1 gene or a deletion of the gene. 
No spontaneous FMR1 full mutations have been reported. 
A study by Hall et al indicated that in fragile X syndrome, the microstructure of white matter is abnormal in areas of the inferior longitudinal and uncinate fasciculi. The study, included 20 patients with fragile X syndrome and 20 matched controls, found a significant increase in fractional anisotropy in the left and right inferior longitudinal fasciculi, the right uncinate fasciculus, and the left cingulum hippocampus, in the fragile X syndrome group, as well as a significant reduction in mean diffusivity in the right inferior longitudinal fasciculus. The investigators stated that the abnormalities probably result from inefficient synaptic pruning, caused by decreased or absent FMRP. 
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