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Vol. 16: Summer, 1998

Management of Common Genetic Disorders

Fragile X Syndrome
  • Introduction

    Fragile X syndrome is the most common cause of inherited mental retardation with an incidence of approximately 1 in 2000 male, and 1 in 2500 female, live births. The carrier frequency in females is 1/259 and in males is 1/755. Fragile X syndrome is an X-linked disorder and occurs with equal frequency in all ethnic groups. Fragile X syndrome is responsible for approximately 10% of all cases of inherited mental retardation and 30% of cases of X-linked mental retardation.

    The gene responsible for fragile X syndrome is located on the X chromosome and is known as the Fragile X Mental Retardation 1 (FMR1) gene. Within the FMR1 gene is a specific region of CGG repeats. Individual with fewer than 40 repeats are not at risk to pass on fragile X syndrome to their offspring. Individuals with 55 to 200 repeats are said to carry the FMR1 premutation. Male individuals with more than 200 repeats have fragile X syndrome. Females with more than 200 repeats have a 50-70% risk to have a low or borderline IQ and a 30-50% chance to have a normal IQ. Approximately 60% of females with more than 200 repeats and a normal IQ have learning problems and emotional or behavioral difficulties.

    There are a few reports in the literature documenting fragile X syndrome due to deletions of the FMR1 gene, but the vast majority of cases are the result of expansion of the CGG triplet repeat within the FMR1 gene. Expansion occurs when the gene mutation is passed from the mother to the child.

    If a mother carries the gene mutation, she is at a 50% risk to pass the gene mutation on to her child. If a father carries the gene premutation, he will pass the gene mutation on to his daughters in the premutation state. None of his sons will inherit the gene mutation.

    The FMR1 gene produces the FMR1 protein (FMRP). In individuals with more than 200 repeats, the gene usually becomes methylated resulting in the gene being turned off. When the FMR1 gene is turned off, FMRP is not produced. It is the lack of FMRP that causes the cognitive features and connective tissue findings of fragile X syndrome.

  • Clinical Features

    The physical features for males with fragile X syndrome include prominent ears, macrocephaly, hyperextensible joints, a long face, prominent forehead, high arched palate, macroorchidism, hand calluses, pectus excavatum, scoliosis, and flat feet. However, many of these features develop with age and are not easily distinguishable in young children. The physical features for females with fragile X syndrome include a long face, prominent forehead, hyperextensible finger joints, double jointed thumbs, mitral valve prolapse, soft skin, and flat feet. These characteristics are usually more prominent when an intellectual deficit is present.

    Most males with fragile X syndrome have moderate mental retardation with an IQ ranging from 40 to 60. However, 13% of males with the full mutation have been reported to have an IQ above 70 (non retarded range). Young boys typically present with hypotonia, multiple ear infections, delayed language development, attention deficit disorder with or without hyperactivity, hand flapping, hand biting, gaze avoidance, and perseveration in speech and behavior. They may also present with a history of tantrums, irritability, sleep problems, and hyperarousal to a variety of stimuli.

    Approximately 20% of individuals with fragile X syndrome experience partial or generalized seizures. Severely affected young girls with fragile X syndrome may present like the boys. Others may have more subtle features including emotional difficulties such as extreme shyness and poor eye contact, social anxiety, selective mutism, mood swings, and have attention problems, problems with math, and tactile defensiveness. Some fragile X syndrome girls experience precocious puberty.

  • Common Medical Complications

    Each child with fragile X syndrome should be monitored carefully for otitis media, as many require PE tubes. Regular audiological exams should be done. A pediatric ophthalmologic exam is recommended to rule out strabismus, nystagmus, or myopia. Neurological evaluation may be warranted if seizures develop. A cardiology evaluation is indicated if there are signs or symptoms of mitral valve prolapse with insufficiency.

    Young girls with fragile X syndrome present with a wide spectrum of findings which may include mental retardation and autistic like features, extreme shyness and anxiety which occasionally leads to selective mutism. In addition, they may have connective tissue problems similar to those found in males, such as scoliosis and mitral valve prolapse. Even those with normal IQ may have learning disabilities related to executive function deficits. This may lead to attention problems, poor topic maintenance, tangentiality in speech, and impulsivity.

    Individuals with fragile X syndrome may benefit from a multidisciplinary approach to intervention. This includes specific medications for ADHD, occupational therapy with an emphasis upon sensory integration therapy, speech and language therapy, augmentative communication or assistive technology aids, and partial or full inclusion in the regular classroom.

    Adolescents and adults with fragile X syndrome have unique problems that need to be addressed through ongoing medical and therapeutic approaches. These may include an increase in aggressive behavior, development of psychosis, heightened anxiety, sexuality issues, and difficulties around separation from parents. Often individuals dealing with these issues will benefit from counseling intervention provided by a professional who is experienced with working with those who have disabilities. In addition, specific medications are helpful in addressing these problems.

    Vocational planning is also important in the adolescent years as is transition into the workplace during young adulthood. The strengths of affected individuals (good memory, aptitude for rote and repetitive tasks, social skills, sense of humor, and computer skills) can be used for vocational planning.

  • Conclusion

    Lifelong monitoring of health status, including mental health, for all patients diagnosed with fragile X syndrome is suggested. Life span is usually normal for these individuals. With changes occurring in society which promote inclusion of persons with disabilities, individuals with fragile X syndrome are likely to be cared for in a wide variety of medical settings.

  • References:

    • Fragile X Syndrome: Diagnosis, Treatment, and Research. Second Edition. Johns Hopkins University Press, 1996. Edited by Randi Jenssen Hagerman, M.D. and Amy Cronister Silverman, M.S

    • Health supervision for children with fragile X syndrome. Committee on Genetics, Pediatrics 98(2): 297-300, 1996

Contributed by Louise Gane, MS

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131


Table of Contents:
Management of Common Genetic Disorders

Introduction
Achondropasia
Down Syndrome / Trisomy 21
Fragile X Syndrome
Marfan Syndrome
Neurofibromatosis
Turner Syndrome
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Bob McCurdy