Doctor123.org

Fragile X Syndrome, Pediatric

Basics

Description

- Developmental/behavioral history - Motor delay due to hypotonia - Speech may be absent to minimally affected. - Autism (60% of males with full mutation) - Severe intellectual disability in males (average IQ of males with the full mutation is 41, with range of 30-55) - Borderline or mild intellectual disability in 50% of females with the full mutation (IQ range 70-85) - Tantrums occur around age 2 years. - Hyperactivity can be severe. - Obsessive and compulsive behaviors - Often requires routine for daily activities - Social anxiety: Patients are shy and easily overwhelmed by noisy environments.

- Growth parameters - Height, weight, and head circumference

- Echocardiogram if cardiac exam is consistent with MVP (usually in adults) - Aortic root dilation may be seen but typically does not progress or require specific treatment - Evaluate for hypertension. - Assess for seizure activity. - Developmental evaluations - Feeding assessment in infants - Education planning - Speech and language - Hearing assessment - Occupational and physical therapy - Behavioral/neuropsychological testing

- No specific medications are available. - Some medications are used to treat specific symptoms in individual patients: - Medications for hyperactivity (e.g., methylphenidate, clonidine, others) - Selective serotonin reuptake inhibitors (e.g., fluoxetine) for obsessive and compulsive behaviors, social phobia, anxiety, and depression - Atypical antipsychotic medications (e.g., risperidone) for psychosis or paranoia - Valproic acid or carbamazepine for seizures and/or mood stabilization

- Surgery/other procedures - Myringotomy tubes if with frequent ear infections and/or conductive hearing loss - Inguinal hernia repair, if present - Strabismus repair, if necessary - Corrective lenses for refractive errors

  • Most common cause of inherited intellectual disability (ID)
  • Caused by mutations in the FMR1 gene on chromosome Xq27.3

Epidemiology

  • Affects ~1 in 4,000-6,000 in males; prevalence in females is ~1/2 that in males
  • Carrier prevalence in females for FMR1 premutation is 1:382 and for intermediate allele(s) is 1:143

Risk Factors

Genetics

  • Caused by loss-of-function mutations in the FMR1 gene on chromosome Xq27.3
  • >99% of affected individuals have a trinucleotide (CGG) repeat expansion (>200 repeats) within the 5' untranslated region of the FMR1 gene.
  • Repeat size categories (based on guidelines from the American College of Medical Genetics):Normal number of repeats: 5-44Intermediate ("gray zone"): 45-54Premutation: 55-200Full mutation: >200
  • Other FMR1 gene mutations may rarely occur (<1% cases).
  • Fragile X syndrome is inherited in an X-linked manner.
  • Fragile X is a CGG trinucleotide repeat disorder that shows anticipation, in which the phenotype can be more severe in subsequent generations due to an expansion in the number of CGG repeats.
  • Expansion only may occur in the germline of mothers who carry a premutation range repeat allele of FMR1.Expansion does not always occur in offspring of female premutation carriers. In general, the larger the number of CGG repeats (>50), the higher the probability that expansion to a full mutation will occur.
  • A male with a premutation will pass on the premutation to 100% of his daughters and none of his sons.
  • Females with a full mutation are typically less severely affected than males because their 2nd FMR1 allele is typically normal and, assuming random X-inactivation occurs, produces variable amounts of fragile X mental retardation protein (FMRP).
  • Males with mosaicism for the FMR1 full mutation (some cells with the full mutation and other cells with the premutation) are generally less severely affected (average IQ 60) relative to males with the full mutation in all the cells
  • Patients with larger chromosomal deletions involving FMR1 and other nearby genes typically have a more severe phenotype

General Prevention

  • Prenatal diagnosis by chorionic villous sampling (~10-12 weeks' gestation) or amniocentesis (~16-20 weeks' gestation) is possible for at-risk pregnancies.
  • Preimplantation genetic diagnosis in the setting of in vitro fertilization is possible for at-risk couples when a familial FMR1 mutation is known.

Pathophysiology

Residual FMRP protein levels directly correlate with the severity of fragile X syndrome manifestations:

  • Absence of FMRP results in characteristic craniofacial, neurologic, and connective tissue abnormalities.
  • Decreased FMRP levels may cause long-term depression of hippocampal synaptic transmission via specific glutamate receptors, with resulting behavioral and neuronal phenotypes.

Commonly Associated Conditions

Other FMR1-related disorders include fragile X-associated tremor/ataxia syndrome (FXTAS) and premature ovarian insufficiency (POI):

  • FXTAS can be seen in older (age >50 years) male and female premutation carriers. Clinical features include intention tremors, abnormal gait with frequent falling, cerebral atrophy, and memory deficits.
  • POI can be seen in 20-25% of female premutation carriers, with menopause occurring prior to age 40 years.

Diagnosis

History

  • Birth/neonatal historyNormal to increased birth weightMay have large head circumference at birthFeeding problems and frequent emesis due to gastroesophageal reflux may occur but improves with growth.Irritability may result from sensory integration difficulties and tactile defensiveness.
  • Past medical historyStrabismus and hyperopia occur in 40%Frequent ear infections in 60%: Conductive hearing loss is possible.Mitral valve prolapse (MVP) and aortic root dilation can occur, typically in adults.Seizures occur in ~20% of children and may resolve by adolescence.Periventricular heterotopia seen on magnetic resonance imaging (MRI)Pes planusScoliosis
  • Developmental/behavioral historyMotor delay due to hypotoniaSpeech may be absent to minimally affected.Autism (60% of males with full mutation)Severe intellectual disability in males (average IQ of males with the full mutation is 41, with range of 30-55)Borderline or mild intellectual disability in 50% of females with the full mutation (IQ range 70-85)Tantrums occur around age 2 years.Hyperactivity can be severe.Obsessive and compulsive behaviorsOften requires routine for daily activitiesSocial anxiety: Patients are shy and easily overwhelmed by noisy environments.
  • Family historyFragile X syndromeIntellectual disability or autism, especially in males related through the maternal sideTremors or ataxia developing >50 yearsPremature ovarian insufficiency in females <40 yearsNo male-male transmission

Physical Exam

  • Growth parametersHeight, weight, and head circumference
  • Characteristic facial featuresLarge head, prominent foreheadLong faceLarge and protruding earsHigh palateProminent chin (after puberty)
  • Murmur or midsystolic click (MVP)
  • Large testicles (after puberty)
  • Joint hypermobility, pes planus, scoliosis
  • Skin often feels soft and smooth

Diagnostic Tests & Interpretation

Lab

Initial Lab Tests

  • Consider FMR1 mutation testing in the following:Males or females with features of autism, developmental delays, or intellectual disabilityMales or females with clinical findings consistent with fragile X syndromeFamily history of fragile X syndrome, recurrent intellectual disability or autism, especially through the maternal sideMales or females with tremor and/or ataxia developing age >50 yearsFemales with premature ovarian insufficiency age <40 years
  • Southern blot or polymerase chain reaction (PCR)-based analyses are the 1st-line genetic tests to determine if there is a repeat expansion and define the number of CGG repeats within the FMR1 gene.

Follow-Up Tests & Special Considerations

  • Methylation status can be determined by using a restriction enzyme that selectively cuts nonmethylated DNA or by methylation-sensitive PCR techniques. This may be considered for higher functioning males with a full mutation to establish their degree of FMR1 methylation.
  • Standard karyotype analysis will typically not be able to detect the repeat expansion.
  • If the patient has many clinical features of fragile X syndrome and Southern blot analysis is normal, consider further molecular techniques to detect point mutations or whole/partial FMR1 gene deletions.

Diagnostic Procedures/Other

  • Echocardiogram if cardiac exam is consistent with MVP (usually in adults)
  • Aortic root dilation may be seen but typically does not progress or require specific treatment
  • Evaluate for hypertension.
  • Assess for seizure activity.
  • Developmental evaluationsFeeding assessment in infantsEducation planningSpeech and languageHearing assessmentOccupational and physical therapyBehavioral/neuropsychological testing

Differential Diagnosis

  • In early childhood, the symptoms of fragile X syndrome are often nonspecific.
  • Other genetic syndromes with overlapping features include the following:Fragile XE syndrome (FRAXE): Patients have a milder degree of intellectual disability as well as less specific physical characteristics compared to patients with typical fragile X syndrome (FRAXA). Mutations of FMR2 on Xq28 are associated with FRAXE.Sotos syndrome: Patients have overgrowth (macrocephaly), intellectual disability, behavioral abnormalities, and cardiac and renal defects. Mutations or deletions of NSD1 are causative of this syndrome.Abnormal parent-specific imprinting of chromosome 15q11-q13:Paternal chromosome affected: Prader-Willi syndrome-infantile hypotonia, obesity, hyperphagia, developmental delay, cognitive deficits, and behavioral abnormalitiesMaternal chromosome affected: Angelman syndrome-severe developmental delay or intellectual disability, minimal to no speech development, gait ataxia and/or tremulousness of the limbs, and inappropriate happy demeanor that includes frequent laughing, smiling, and excitabilityA range of other genes is now recognized to cause syndromic autism and X-linked intellectual disability. PTEN mutations can be associated with macrocephaly and autism. Clinical diagnostic testing either individually or through gene panels is available (www.genetests.org).

Treatment

Medication

  • No specific medications are available.
  • Some medications are used to treat specific symptoms in individual patients:Medications for hyperactivity (e.g., methylphenidate, clonidine, others)Selective serotonin reuptake inhibitors (e.g., fluoxetine) for obsessive and compulsive behaviors, social phobia, anxiety, and depressionAtypical antipsychotic medications (e.g., risperidone) for psychosis or paranoiaValproic acid or carbamazepine for seizures and/or mood stabilization

Additional Treatment

General Measures

  • Treatment is aimed at supportive measures.
  • Per American Academy of Pediatrics (AAP) guidelines, routine evaluation for ocular, ENT, skeletal, and neurologic abnormalities. Refer to appropriate specialists as needed.
  • Early developmental servicesPhysical therapy for joint laxity/hypotoniaOccupational therapySpeech and language therapySocial integration therapy
  • Some patients do well in a mainstream school with appropriate support, whereas others require a school for children with special needs.
  • Behavioral therapies involve avoidance of overstimulation and providing positive reinforcement.

Additional Therapies

  • Experimental therapiesGlutamate receptor antagonists, gamma-aminobutyric acid (GABA) receptor agonists, minocycline, carnitine, valproic acid, and lovastatin have shown some improvement in the neurologic and behavioral symptoms.
  • Surgery/other proceduresMyringotomy tubes if with frequent ear infections and/or conductive hearing lossInguinal hernia repair, if presentStrabismus repair, if necessaryCorrective lenses for refractive errors

Ongoing Care

Follow-up Recommendations

Patient Monitoring

  • Regular follow-up with a behavioral and developmental pediatrician as well as a psychiatrist/psychologist is recommended for patients with behavioral problems.
  • Hypertension can occur in adults with fragile X syndrome. Therefore, annual blood pressure and cardiac exam should be performed. Hypertension can be treated with typical medications used in the general population. If hypertension is refractory to treatment, evaluate for other causes of high blood pressure (e.g., renal).

Diet

No specific dietary requirements.

Prognosis

Most patients generally have a normal lifespan.

Additional Reading

  • American Academy of Pediatrics. Health supervision for children with fragile x syndrome. Pediatrics. 2011;127(5):994-1006. [View Abstract]
  • Bagni C, Oostra BA. Fragile X syndrome: from protein function to therapy. Am J Med Genet A. 2013;161A(11):2809-2821. [View Abstract]
  • Fragile X mental retardation syndrome. Online Mendelian Inheritance in Man. http://www.omim.org/entry/300624. Accessed December 3, 2014.
  • Monaghan KG, Lyon E, Spector EB; American College of Medical Genetics. ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med. 2013;15(7):575-586. [View Abstract]
  • Saul RA, Tarleton JC. FMR1- related disorders. In: Pagon RA, Adam MP, Bird TD, et al, eds. GeneReviews⢠[Internet]. Seattle, WA: University of Washington, Seattle; 1993-2013. [View Abstract]

See Also: National Fragile X Foundation: www.fragilex.org

Codes

ICD09

  • 759.83 Fragile X syndrome

ICD10

  • Q99.2 Fragile X chromosome

SNOMED

  • 613003 fragile X syndrome (disorder)

FAQ

  • Q. Why is it called "fragile X syndrome"?
  • A. Early cytogenetic studies of male patients with intellectual disability identified a site on the X chromosome that would appear constricted when the patient's cells were grown with special culture techniques to induce "fragile" sites.
  • Q. How many repeats are necessary to cause the full mutation resulting in fragile X syndrome?
  • A. More than 200 repeats.
  • Q. What are typical facial features seen in patients with fragile X syndrome?
  • A. Prominent forehead, long face, protruding ears, and a prominent chin.
  • Q. When does the macroorchidism associated with fragile X syndrome typically develop?
  • A. After puberty.