AUTHOR INFORMATION

Section 1 of 11

Authored by Jennifer Jewell, MD, Clinical Assistant Professor, Department of Pediatrics, University of Vermont School of Medicine, Pediatric Hospitalist, The Barbara Bush Children's Hospital at Maine Medical Center

Jennifer Jewell, MD, is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, Massachusetts Medical Society, and Sigma Xi

Edited by Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Jennifer Jewell, MD
Editor's Email:	Michael Fasullo, PhD

eMedicine Journal, September 13 2006, VOLUME 7, Number 9

INTRODUCTION

Section 2 of 11

Background: Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited mental retardation and, after trisomy 21, is the second most common cause of genetically associated mental deficiencies. In 1943, Martin and Bell investigated a family with multiple male relatives who had mental retardation. They were able to link the cognitive disorders to an unidentified mode of X-linked inheritance. In 1969, Lubs discovered excessive genetic material extending beyond the long arm of the X chromosome in affected males and in their unaffected female relatives. 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.

Pathophysiology: Cognitive, behavioral, and neuropsychological difficulties predominate the clinical picture. These signs are especially important in alerting physicians, parents, and teachers to deficits exhibited by preschool and elementary school children, ages 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), attention deficits, depressed affect, mental retardation with IQ typically 35-70, 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 related partially to each individual’s environment, maternal psychopathology, and available educational/therapeutic opportunities, especially for affected males. In addition, physical signs associated with fragile X syndrome exist; 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 are craniofacial, genital, and musculoskeletal.

Fragile X-associated tremor/ataxia syndrome (FXTAS) has recently been described in older men and women with premutations in the fragile X mental retardation (FMR1) gene. Full mutations of this gene result in fragile X syndrome. Clinical features of FXTAS include cerebellar ataxia, autonomic dysfunction, severe tremor, and other signs of neurodegeneration such as memory loss, anxiety, and irritability.

Frequency:

• In the US: Conservative estimates report that fragile X syndrome affects approximately 1 in 4000 males and 1 in 8000 females. The rate of the female carrier state has been estimated to be as high as 1 in 250; the male carrier state is estimated to be 1 in 1000. As many as 10% of cases of previously undiagnosed mental retardation in males and 3% of cases of previously undiagnosed mental retardation in females are attributed to fragile X syndrome.

• Internationally: 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 mental retardation and cognitive/behavioral/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/ethnic diversity or to diagnostic technology is unclear.

Sex:

• Two to four times as many females carry the gene abnormality as males, but only about one third of females carrying the abnormal gene show decreased intelligence.

• Females with the disorder are more likely to have less impairment ability and less obvious physical features. Males with the disorder are more likely to be sensitive to environmental factors.

• The pattern of inheritance most closely resembles X-linked dominant with variable penetrance. Occasionally, because the complex genetics of the disorder, a female will be severely affected.

Age:

• Fragile X syndrome is an inherited disorder and is present at birth.

• Diagnosis is typically made at a younger age if the mental retardation is discovered during a prenatal or family history. If physicians are acquainted intimately with children's families, 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.

CLINICAL

Section 3 of 11

History:

• Significant family, developmental, cognitive, and neuropsychological histories are keys to diagnosis. Infrequently, unusual musculoskeletal anomalies, feeding difficulties, and recurrent nonspecific medical problems may be reported.

• Family history


• • Screening and diagnosis in utero or during infancy is usually the result of a family history notable for multiple male relatives with mental retardation.

  • Other clues to the diagnosis include a mother with learning disabilities/mental retardation or family members with ataxia and tremors.

  • Female infertility secondary to premature ovarian failure and increased rates of dizygotic twinning have recently been discovered to be more common in fragile X carriers and may provide another clue to the diagnosis.
  
  
  
• Developmental history


• • During infancy, developmental milestones are achieved as expected or are delayed slightly.

  • After the first year of life, however, 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 impaired significantly.
  
  
  
• Cognitive history


• • IQ frequently indicates mild-to-severe mental retardation (20-70). Females and less-affected males may have IQs approaching 80.

  • IQ may be higher in childhood than in adulthood because of slowing of mental development and difficulties with IQ test-taking rather than loss of intellect.
  
  
  
• Neuropsychological history


• • Patients have many neuropsychological features, including depression and anxiety.

  • Autisticlike behavior (particularly, poor eye contact and hand biting or hand flapping) is present in between 16 and 25% of patients with fragile X syndrome. However, social conversation abilities may be present even in patients with autisticlike behavior. Molecular investigation for fragile X syndrome is the single laboratory test proven to aid in definitively diagnosing patients with infantile autism.

  • Universal behavioral features of males with fragile X syndrome are similar to those observed in patients with attention deficit hyperactivity disorder (ADHD)—aggressive tendencies and attention deficits.

  • Approximately 20% of patients have a seizure disorder, with nearly half of those having persistent seizures requiring anticonvulsant therapy.

  • Many children have difficulty when routines are altered.

  • Some people with fragile X syndrome display features of obsessive-compulsive disorder and/or sensory integration disorder.
  
  
  
• Musculoskeletal features: Features include pes planus, pectus excavatum, joint laxity, scoliosis, and joint dislocation.



• Feeding difficulties: Patients may manifest symptoms of reflux/vomiting and, on rare occasion, failure to gain weight during infancy and childhood.



• Recurrent nonspecific medical problems


• • Patients may have recurrent sinusitis, otitis media, and decreased visual acuity.
  
  
  
  • During the history taking, ask about apnea (de Vries, 1998).
  
  
  

Physical:

• The phenotype of fragile X syndrome is difficult to diagnose in prepubertal children. Most physical examination findings are notable only after onset of puberty.


• • Growth: Childhood growth is marked by an early growth spurt. However, adult height is often average or slightly below average.
  
  
  
  • Craniofacial: Adolescent and adult patients have a long thin face with prominent ears, facial asymmetry, a head circumference greater than the 50th percentile, and a prominent forehead and jaw.
  
  
  
• Mouth: The mouth has dental overcrowding and a high-arched palate.



• Ears: Ears are typically large and may protrude.



• Eyes: Strabismus is frequently noted.



• Extremities: Hands and feet manifest nonspecific findings, including hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus.



• Back and chest: Pectus excavatum and scoliosis are frequent findings.



• Genitals: Macroorchidism is universal in adult 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.



• Cardiac: A heart murmur or click consistent with mitral valve prolapse often is auscultated and requires cardiology referral.

Causes:

• 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 extending beyond the long arm at the highly conserved band Xq27.3. This constriction and thin strand produces 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 (FMR1) gene, is currently unclear but is believed to play a role in normal brain development. 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 5-55 CGG repeats in the first exon at the 5’ end of band Xq27.3. A span of 65-200 repeats is known as a premutation, whereas more than 200 repeats is a full mutation. Full mutation results in hypermethylation of the cysteine bases and restricts protein binding, leading to gene inactivation. 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 all males with fragile X syndrome have the premutation or fragile X syndrome themselves. 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, no increase in the CGG triplets exists. 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. 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.

DIFFERENTIALS

Section 4 of 11

Attention Deficit Hyperactivity Disorder
Ehlers-Danlos Syndrome
Marfan Syndrome
Pervasive Developmental Disorder
Pervasive Developmental Disorder: Autism
Pervasive Developmental Disorder: Rett Syndrome

Other Problems to be Considered:

Learning disabilities
Lujan syndrome

WORKUP

Section 5 of 11

Imaging Studies:

• Radiography of the spine is recommended to evaluate for scoliosis.



• Echocardiography is recommended to rule out mitral valve prolapse.

Other Tests:

• Cytogenetics


• • Cytogenetic testing for fragile X syndrome is not as sensitive as molecular testing, with a false-negative result rate of approximately 20%. Thus, DNA testing for fragile X syndrome is recommended.
  
  
  
  • Karyotyping may reveal other chromosomal anomalies, and both a standard karyotype and DNA testing are suggested to be performed when a possible diagnosis of fragile X syndrome is considered.
  
  
  
• Molecular genetics: The criterion standard diagnostic test uses molecular genetic techniques. 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.


• • Southern blot analysis provides a more accurate estimation of the number of CGG triplet repeats if a full mutation is present (with a large CGG expansion). It can also be used to evaluate the degree of methylation at the CGG repeat site.
  
  
  
  • PCR is faster, requires a minimal sample, and is less expensive than Southern blot analysis. Additionally, PCR gives a more accurate estimation of the number of CGG triplet repeats if a premutation is present (with small-to-moderate increases in CGG repeats.) Recent success with fluorescent methylation-specific PCR and GeneScan analysis may further expand diagnostic options.
  
  
  
• A comprehensive developmental evaluation by a speech/language therapist, physical therapist, and occupational therapist is recommended to assess weaknesses and to identify areas where improvement is needed most. As the patient matures, repeat evaluation may be necessary.



• Ophthalmology examinations are required.



• Routine auditory examinations are advised; otolaryngology referral for chronic otitis media and evaluation for pressure equalization (PE) tube placement are recommended.

TREATMENT

Section 6 of 11

Medical Care:

• Workup and diagnosis can be done on an outpatient basis.



• Routine care involves treating the medical problems that these patients commonly experience; these include gastroesophageal reflux, sinusitis, and otitis media.



• During infant and early childhood healthcare maintenance visits, focus examination on possible hip dislocations, hernias, and hypotonia.

Consultations:

• Genetic specialist



• Speech and language therapist



• Occupational and physical therapist



• Special education professional: Consultation with a special education professional is appropriate for level of cognitive functioning, sensory integration therapy for behavior problems, ADHD symptoms, and aggressiveness.



• Psychology or behavioral specialist: This consultation is important to assist families with methods for decreasing negative behavior.



• Neurologist: Consult a neurologist if seizures persist.

• Cardiologist

• Otolaryngologist: Patients with chronic sinusitis and chronic otitis media need an evaluation by an otolaryngologist.

• Ophthalmologist: An ophthalmologic referral is important for patients with strabismus.

• Gastroenterologist

• Orthopedic surgeon
  • Patients are frequently assessed by an orthopedic surgeon for abnormal gait caused by pes planus, which is managed with orthotic inserts or orthopedic shoes.

  • Although scoliosis is rarely severe enough to warrant orthopedic surgical intervention, all patients should have a spine film to quantify the degree of scoliosis if clinically observed. Referral to an orthopedic surgeon is required if curvature is significant.

Diet:

• A special diet is indicated in infants with significant gastroesophageal reflux. In this case, thickened feeds may decrease the incidence of reflux; otherwise, no special diet is indicated.

Activity:

• No limitations of activity are indicated.

MEDICATION

Section 7 of 11

The results of folic acid supplementation to curb the inattention and aggressiveness in prepubertal males are controversial; thus, folic acid supplementation is currently not the standard of care. No effect has been observed in adults treated with folic acid.

FOLLOW-UP

Section 8 of 11

Further Outpatient Care:

• Routine outpatient care and immunization schedule



• Family counseling to assist in behavior modification strategies

In/Out Patient Meds:

• Stimulants (eg, methylphenidate, dextroamphetamine) have been used for attention deficits in the doses prescribed for patients with ADHD. Responses are variable.



• Antiseizure, antireflux, antidepressants (eg, SSRIs), sleep (eg, trazodone, melatonin), and mood stabilizing medications are useful for patients with these symptoms.

Complications:

• Scoliosis



• Mitral valve prolapse (most frequently encountered cardiac defect)

Prognosis:

• Life expectancy is normal.

Patient Education:

• Family members should attempt behavior modification techniques and be involved with a counselor to assist with appropriate modes of discipline.



• Adult patients should reside in the least restrictive environment that is safely acceptable to foster independent living.



• Patients should receive special education classes that are appropriate for cognitive ability. Work programs should be sought for those patients who are trainable.



• For more information by mail, contact the Fragile X Foundation, PO Box 300233, Denver, CO 80203.



• For information on the Internet, contact the Fraxa Research Foundation or the National Fragile X Foundation.

MISCELLANEOUS

Section 9 of 11

Special Concerns:

• Prenatal screening: Because fragile X syndrome is underdiagnosed, has a high prevalence, and is inheritable, preconceptual and antenatal molecular genetic screening is encouraged for women as outlined below.


• • Obstetricians and primary care providers have access to such women and should recommend screening in high-risk cases. Additionally, a geneticist and/or a genetic counselor should be available to provide accurate information to families if screening is positive for fragile X mutations.
  
  
  
  • Southern blot analysis, PCR, and immunocytochemical testing are used for diagnosing maternal, pre-implantation, and fetal premutations; full mutations; and proteins.
  
  
  
  • Fetal testing may be performed by chorion villus sampling or amniocentesis and incurs the risks associated with these procedures.
  
  
  
  • Recommending prepregnancy or prenatal fragile X syndrome screening to women with a family history of fragile X syndrome or mental retardation and to women with learning difficulties and/or mental retardation is advisable. All women who are known carriers of the premutation or full mutation should be offered prenatal testing.
  
  
  
  • Genetic counseling is important for women who have premutations and full mutations or who are carrying an affected child.
  
  
  

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is not associated with fragile X syndrome?

A: Long face
B: Joint laxity
C: Mental retardation
D: Spasticity of muscles during infancy
E: Seizures

The correct answer is D: Infants with fragile X syndrome are hypotonic. Long face, laxity of joints, mental retardation, and seizures are common.

CME Question 2: Which of the following scenarios is most likely to result in a child with fragile X syndrome?

A: The son of a father with a premutation
B: The daughter of a father with a premutation
C: The son of a mother with a premutation
D: The daughter of a mother with a premutation
E: The daughter of a father with a full mutation

The correct answer is C: The premutation is dynamic during oogenesis and often expands to a full mutation, resulting in a son with fragile X syndrome.

Pearl Question 1 (T/F): Aortic stenosis is the most frequently encountered cardiac defect in patients with fragile X syndrome.

The correct answer is False: Mitral valve prolapse is the most frequently encountered cardiac defect.

Pearl Question 2 (T/F): An extra chromosome is the genetic abnormality that causes fragile X syndrome.

The correct answer is False: Increased CGG repeats and increased methylation at band Xq27.3 are the genetic abnormalities that cause fragile X syndrome.

Pearl Question 3 (T/F): The culture medium used in cytogenetic diagnostic testing for fragile X syndrome must be folate- and thymidine-depleted.

The correct answer is True: The culture medium must be folate- and thymidine-depleted.

Pearl Question 4 (T/F): Fragile X syndrome is the most common inherited cause of mental retardation.

The correct answer is True: Fragile X syndrome is the most common cause of inheritable mental retardation and the second most common cause of genetically associated mental retardation, following trisomy 21.

BIBLIOGRAPHY

Section 11 of 11

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