F

Febrile Seizure

What is a Febrile Seizure?
Who is at Risk for Febrile Seizures?
How are Febrile Seizures Diagnosed?
How is a Febrile Seizure Treated?
What are the Complications of Febrile Seizures?
Can a Febrile Seizure be Prevented?

What is a Febrile Seizure?
A seizure is described as an involuntary spasm of muscles. Febrile seizures occur in developmentally and neurologically normal children between ages 6 months to 5 years of age who are also experiencing a fever and who are without an infection of the central nervous system. Febrile seizures occur in 2-5% of all children under 5 years of age. While frightening, they are generally benign events.
Two classifications exist:
. The simple febrile seizure is a single, brief episode associated with a fever and it resolves within 15 minutes.
. The complex febrile seizure lasts longer than 15 minutes and/or it recurs within a 24 hour period.

Who is at Risk for Febrile Seizures?
Three risks have been identified as possible predisposing factors for febrile seizures: height and duration of the temperature, a first degree relative with a history of febrile seizures, and if it occurs in association with vomiting and diarrhea.
One third of children will have a recurrence of a febrile seizure, more commonly between 12 – 24 months of age.
Four risks have been identified for recurrence of febrile seizures:
. First degree relative with a history of febrile seizures,
. Age of onset less than 18 months of age,
. Temperature greater than 104 degrees Fahrenheit (40 degrees Celsius), and
. Rapid onset (less than one hour between the onset of the fever and occurrence of a seizure).

How are Febrile Seizures Diagnosed?
A practitioner will perform a history and physical exam and determine if any other tests would be helpful to assess the problem. No routine blood tests are necessary to diagnose a febrile seizure.
Lumbar puncture should be performed if an infection of the nervous system is suspected or if a child is under 18 months of age and your practitioner has a concern for a nervous system infection. An electroencephalogram (EEG) is not indicated unless a complex febrile seizure occurs or if a child has a neurological abnormality. An MRI is reserved for difficult cases; for example, seizures with neurological changes and/or changes on an EEG exist.

How is a Febrile Seizure Treated?
A fever is best treated with antipyretic medication (Acetaminophen and/or Ibuprofen) and administered prior to an event. If the seizure occurs, avoid danger to the child by assuring safe placement of the head and avoiding choking. Parents should activate their local emergency medical system (i.e. call 911) if the child has a loss of consciousness for greater than 1 minute. Treatment of a single febrile seizure is not indicated since only one third of children will have a second febrile seizure.
Typically an anticonvulsant medication is chosen for children with a known underlying neurological abnormality or if a recurrent febrile seizure is prolonged. The onset of a febrile seizure does not occur with every fever; therefore, treatment is specific to the case and chosen by the practitioner and parents. Intermittent therapy has been used. Most of the medications that have been studied do have side effects (including sedation, aggressiveness, euphoria, cognitive changes, weight changes, blood abnormalities etc.). The medications include diazepam, phenobarbital, and valproate. Diazepam has been the most favorable and can be administered orally or rectally, Two drugs are ineffective in preventing recurrent febrile seizures phenytoin and carbamazepine.

What are the Complications of Febrile Seizures?
Febrile seizures do not result in serious complications, including mental retardation, a decrease in IQ, cerebral palsy, neurological damage, epilepsy or learning difficulties. Thus the simple febrile seizure has no long or short term effect. No recommendation to restrict activities exists.

Can a Febrile Seizure be Prevented?
Acetaminophen and Ibuprofen are used to treat fever but have not been proven to prevent a seizure or its recurrence. Nothing has been guaranteed to prevent an initial febrile seizure.

References
Baumann RJ, Duffner PK: Treatment of Children with Simple Febrile Seizures: The AAP Practice Parameter. Pediatric Neurology 2000;23 (1):11-17.
Shinnar S, Glauser TA: Febrile Seizures. Journal of Child Neurology 2002;17:S44-S52.
Provisional committee on Quality Improvement Subcommittee on Febrile Seizures: Practice Parameter: The Neurodiagnostic Evaluation of the Child with a First Simple Febrile Seizure. Pediatrics/AAP 1996:71-74.
Hampers L: Diagnosis and Management of Febrile Seizures. Pediatric Emergency Medicine at The Children’s Hospital, Denver Colorado p 1-8.
Reviewed by: Sunit Gill MD
This Article contains the comments, views and opinions of the Author at the time of its writing and may not necessarily reflect the views of Pediatric Web, Inc., its officers, directors, affiliates or agents. No claim is made by Pediatric Web, the Author, or the Author’s medical practice regarding the effectiveness and reliability of the statements contained herein and such individuals and entities disclaim any and all liability for the comments and statements contained in this Article and for any use or misuse of the statements made in this article in any specific medical situations. Further, this Article is intended to be general in nature and shall not be considered medical advice. The statements made are not to be utilized to diagnose and/or treat any individual’s medical symptoms. If you or someone you know has symptoms which you believe are similar to this Article, you should discuss such symptoms with your personal physician or other qualified medical practitioner.
Copyright 2012 Pediatric Web, Inc., by Dan Feiten, M.D. All Rights Reserved

Fetal Alcohol Syndrome

What is fetal alcohol syndrome?
What causes fetal alcohol syndrome?
Who gets fetal alcohol syndrome?
How does alcohol cause disease?
What are the common findings?
How is fetal alcohol syndrome diagnosed?
How is fetal alcohol syndrome treated?
What are the complications?
How are the complications of fetal alcohol syndrome prevented?
What research is being done?
Links to additional information
Product Information
General reading

by Randi Hagerman, M.D. Professor of Pediatrics, University of Colorado Health Sciences Center and The Children’s Hospital Denver, Colorado

What is fetal alcohol syndrome?
Fetal alcohol syndrome is a disorder caused by alcohol exposure in the womb. Alcohol interferes with brain development in the fetus. It also causes unusual physical features in the fetus, including facial structure abnormalities and bone growth deficiencies.

What causes fetal alcohol syndrome?
Alcohol is a “teratogen,” meaning it causes birth defects. When a mother drinks alcohol during her pregnancy, the alcohol in the bloodstream enters the fetal circulation and interferes with cell growth and migration. This particularly affects early brain development in the fetus. The growth of bones and organs, including the heart and the kidneys, also can be significantly affected by alcohol exposure in the womb.

Who gets fetal alcohol syndrome?
A fetus exposed to significant amounts of alcohol may be affected with fetal alcohol syndrome; whereas, a fetus exposed to alcohol for limited times during pregnancy may not be as severely affected or show evidence of fetal alcohol syndrome. Both male and female fetuses can be affected.
The disorder affects individuals differently; some individuals have mild behavioral problems or intellectual deficits, while other individuals have more severe complications with bone and organ development. Exposure in the second and third trimester of pregnancy usually leads to full fetal alcohol syndrome; however, exposure in the first trimester may interfere with brain structure. Usually, if a mother ss drinking during the first trimester of pregnancy, it is likely that the fetus will not be significantly affected with fetal alcohol syndrome.

How does alcohol cause disease?
Alcohol interferes with the metabolism of cells, and it may cause early cell death or lack of normal replication or migration.

What are the common findings?
Most children affected with full fetal alcohol syndrome have characteristic facial abnormalities, including a small opening of the eye, underdevelopment of the mid-part of the face, a thin upper lip, and a flat “philtrum” (the part of the face between the upper lip and the bottom of the nose). In addition, individuals may have poor growth of the mandible or the upper jaw. The base of the nose may be underdeveloped, and the nose may be shorter than normal. Alcohol also may cause poor growth of the head so that the head circumference is smaller than normal. In addition, these individuals may have a short stature, and are usually thin.
Alcohol also causes dysfunction of the central nervous system, which may include mental retardation or learning disabilities. Hyperactivity, with a short attention span and poor impulse control, are very common. Depression, anxiety, and panic attacks, along with psychotic thinking, including delusions or hallucinations, also are relatively common, particularly in adolescence and adulthood.
Structural brain changes are not uncommon in individuals affected by fetal alcohol syndrome. Poor development of the “corpus collosum,” the band of fibers in the brain that connects the left and the right side of the brain, is common. In addition, the “cerebellum,” an older area of the brain, may be underdeveloped. Rarely, other more severe brain abnormalities may occur. A limited number of individuals with fetal alcohol syndrome also may experience seizures, particularly in childhood.
Organs may be significantly affected by alcohol exposure in the womb, to include the following:
. Kidneys: May often be small or underdeveloped
. Heart: Can have a defect in the wall between the atria or the ventricles, or more severe malformations
. Eyes: Abnormalities of the vessels in the retina, strabismus (lazy eye), or underdevelopment of the eyeball
. Auditory System: A sensory neural hearing loss may occur, along with frequent ear infections
. Skeletal System: Shortening of the fingers, vertebra, or long bones; scoliosis (curvature of the spine); or underdevelopment of the nails

How is fetal alcohol syndrome diagnosed?
Exposure to alcohol in the womb causes a wide range of abnormalities. The most severe level is Fetal Alcohol Syndrome (FAS). FAS must have a confirmed history of maternal alcohol exposure. For a full diagnosis of FAS, the patient must have the characteristic facial abnormalities, in addition to growth retardation, i.e., a low birth weight for gestational age or height/weight growth parameters less than the 10th percentile.
There also must be evidence of central nervous system neurodevelopmental abnormalities, such as small head size, structural brain abnormalities, or neurological hard or soft signs. Such signs include impaired fine motor skills, a sensory neural hearing loss, poor tandem walking, or poor hand/eye coordination.
Individuals also may be diagnosed with Partial Fetal Alcohol Syndrome (PFAS). A diagnosis of PFAS is confirmed by maternal alcohol exposure, in addition to some of the characteristic facial features, growth retardation, central nervous system neurodevelopmental abnormalities, or a complex pattern of behavioral or cognitive abnormalities.
Typically, these abnormalities are inconsistent with the child’s development level, and cannot be explained by family background or environment. These features can include the following: learning difficulties; deficits in school performance; poor impulse control; problems in social perception; deficits in higher level expressive and receptive language development; poor capacity for abstraction; specific deficits in mathematical skills; or problems in memory, attention, or judgment.
Another alcohol exposure disorder is Alcohol Related Birth Defects (ARBD). ARBD requires the presence of congenital abnormalities, including malformations in the cardiac system, the skeletal system, the kidney system, the eyes, or the auditory system.
The Alcohol Related Neurodevelopmental Disorder (ARND) requires central nervous system neurodevelopmental abnormalities or a complex pattern of behavioral or cognitive abnormalities, including learning disabilities and attention deficit problems. ARND is the mildest form of fetal alcohol syndrome.
Usually, individuals have behavioral problems, such as hyperactivity or learning disabilities, but do not show abnormal facial features, which are typical of alcohol exposure. There is animal and human research indicating that abnormalities can occur in the brain, leading to learning problems or behavioral difficulties, without having abnormal facial features.

How is fetal alcohol syndrome treated?
At the time of birth, newborns exposed to significant levels of alcohol may have severe withdrawal symptoms. In approximately 33% of the cases, seizures may occur. Medication, such as phenobarbital, can be given at the time of birth to control the seizures; however, for many infants, medications are not necessary to treat withdrawal symptoms. It is important to wrap the baby tightly, to dim the lights, to reduce the noise level to avoid overstimulation, to feed the baby frequently, and to massage the baby to help relaxation.
It is possible that the baby may have significant malformations at the time of birth, such as a cleft lip or a cleft palate, and, occasionally, even a neural tube defect can be related to alcohol exposure in the womb. The baby may have problems with feeding and abdominal distention related to alcohol withdrawal. Help with oral feeding may be obtained from an occupational therapist.
It also is important to treat the alcoholism of the mother. A treatment program-including advocacy and psychological support for the mother, help with obtaining services and entitlements, parent skills training, crisis intervention, guidance and feedback, general encouragement, and a substance abuse program-is very beneficial.
Infants and preschoolers with fetal alcohol syndrome disorders should be enrolled in a developmental program that has both language and motor therapy. Hyperactivity and distractibility, which are associated with Attention Deficit Hyperactivity Disorder (ADHD), often arises in preschool. Initially, behavioral techniques should be used to control hyperactivity, both at home and at school. Tantrums and aggression also may occur in preschool. If behavioral interventions are not adequate, then medication may be helpful, even in preschool. Useful medications include clonidine (to decrease hyperarousal) or stimulant medication, such as dextroamphetamine or methylphenidate.
There is some evidence that dextroamphetamine may be more effective than methylphenidate for children with ADHD. Sleep disturbances also may occur, and the “Baby Go To Sleep Tape” may be helpful. Medication, such as clonidine, can be used at bedtime. Melatonin, which is the natural sleep hormone, also may be beneficial.
For the school-age child with a fetal alcohol syndrome disorder, deficits in language and motor development also may continue, and may require individualized speech and language therapy and occupational therapy. Some children overreact to stimuli or have sensory motor integration problems. This can worsen hyperactive and tantrum behavior, and should be treated by a sensory integration occupational therapy program. Most children with fetal alcohol syndrome require special education support. A learning disability teacher can use a multi-sensory approach for teaching academic skills, such as reading or math.
Computers may enhance academic learning and language skills for children with fetal alcohol syndrome. Computer programs may help with visual spatial perceptual skills. Such programs as “KidPix,” which enhances drawing and graphics, or “Blocks in Motion,” which focuses on visual spatial processing, may be beneficial. Additionally, such programs as “Oregon Trails,” “Interactive Journeys,” and “Where in the World is Carmen Sandiego?” use problem solving skills through reading and listening cues, and are helpful for academic progress in math and reading. Programs that enhance writing skills, such as word prediction software, can expand written language abilities.
School-age children with fetal alcohol syndrome usually have problems with ADHD. Stimulant medication, such as dextroamphetamine (Adderall and Dexedrine) or methylphenidate (Ritalin), can be helpful in this age group.
Children who are affected by alcohol exposure in the womb should have a detailed psychological assessment that documents their intellectual abilities or IQ, as well as emotional difficulties. If significant emotional problems, such as anxiety, depression, or mood swings occur, then ongoing counseling should be helpful. Sometimes, if significant anxiety or depression exists, medication, such as Prozac or Zoloft, may be helpful.
If mood swings are a problem, then mood-stabilizing medication, such as Tegretol, Depakote, or risperidone, can be helpful. Usually, medication to treat emotional or behavioral problems work best when combined with counseling by a psychologist or a mental health professional.

What are the complications?
The main complications associated with FAS, PFAS, or ARND are the secondary disabilities that are prominent in adolescence and adulthood. There is a high rate of mental health problems, and 94% of individuals experience these difficulties. The combination of mental health problems, in addition to a high rate of substance abuse, can lead to legal problems.
In a large study of over 400 individuals with fetal alcohol syndrome disorders, conducted in Seattle by Dr. Streissguth and her colleagues, it was found that 32% of adolescents and 42% of adults were jailed for a crime. Alcohol problems also occurred in 42% of adults. This high rate of social problems demands more intensive intervention in childhood to avoid these secondary disabilities.
Individuals also may suffer from complications related to medications. For instance, stimulant medications can decrease appetite and interfere with normal growth when weight loss occurs. Careful monitoring of blood levels and liver function studies are required with some of the mood stabilizers, because they may decrease the white blood cell count or irritate the liver.

How are the complications of fetal alcohol syndrome prevented?
Careful medical follow-up, particularly when individuals are treated with medication, is necessary. When taking medication, individuals should visit their doctor at least two to three times a year.
The prevention of secondary disabilities is a more complicated issue, and it requires intensive treatment from early childhood. Long-term counseling in adolescence and early adulthood, in addition to more intensive vocational training with a job skill trainer, is beneficial. Early education regarding the complications of drug and alcohol use also is important. If these problems develop, an intensive substance abuse program is necessary.

What research is being done?
Research is being conducted regarding the prevention of fetal alcohol syndrome. There is a massive public health program to educate women regarding the problems associated with alcohol use when they are pregnant.
Very little research has been performed regarding the treatment of those individuals who are affected by fetal alcohol syndrome. There is a great need for controlled research regarding psychopharmacological interventions and educational interventions. Animal research has suggested that cholinergic drugs may be beneficial for treating hyperactivity and cognitive deficits; however, these, and other new drugs, have not yet been studied in humans.
Research regarding innovative computer programs that enhance learning, such as the “Fast Forward” program, using a computerized slowing of speech to improve auditory processing deficits, may be helpful. However, these studies also have yet to be conducted.

Links to additional information
National Organization of Fetal Alcohol Syndrome (NOFAS)
1819 H Street NW, Suite 750
Washington, DC 20006
Phone: (202) 785-4585
Fax: (202) 466-6456
E-mail: NOFAS@erols.com
Web: http://www.nofas.org
Family Empowerment Network: Supporting Families Affected by Fetal Alcohol Syndrome and Effects
University of Wisconsin
519 Lowell Hall
610 Langdon Street
Madison, WI 53703
Phone: (800) 462-5254
Fax: (608) 262-6590
E-mail: fen@mail.dsc.wisc.edu
Fetal Alcohol Information Service
P.O. Box 95597
eattle, WA 98145-2597
National Association for Perinatal Addiction Research and Education (NAPARE)
11 E. Hubbard Street 200
Chicago, IL 60611
Fetal Alcohol Education Program
Boston University School of Medicine
1975 Maine Street
Concord, MA 01742
Phone: (978) 369-7713
FAS Family Resource Institute (FAS*FRI)
P.O. Box 2525
Lynnwood, WA 98036
Phone: (800) 999-3429
Fetal Alcohol and Drug Unit
University of Washington
180 Nickerson Street, Suite 309
Seattle, WA 98109
Phone: (206) 543-7155
National Clearing House for Alcohol and Drug Information (NCAID)
P.O. Box 2345
Rockville, MD 20852
Phone: (800) 729-6686

Product Information
The “Baby Go To Sleep” tape may be obtained by calling (800) 537-7748.

General reading
Dorris, M. (1989) The Broken Cord. New York: Harper Collins.
Kleinfeld, J.K. and Wescott, S. (eds.) (1993) Fantastic Antone Succeeds! Experiences in Educating Children with Fetal Alcohol Syndrome. Fairbanks: University of Alaska Press.
Streissguth, A.P. and Kanter, J. (eds.) (1997) The Challenge of Fetal Alcohol Syndrome: Overcoming Secondary Disabilities. Seattle: University of Washington Press.
Streissguth, A. (1997) Fetal Alcohol Syndrome: A Guide for Families and Communities. Baltimore, MD: Paul H. Brooks Publishing.
Hagerman, R.J. (1999) Fetal Alcohol Syndrome. In: Neurodevelopmental Disorders: Diagnosis and Treatment. New York: Oxford University Press.

About the Author
Dr. Hagerman received her M.D. from Stanford Medical School and completed her pediatric residency at Stanford and at the University of California San Diego. She is now a Professor of Pediatrics at the University of Colorado Health Sciences Center and Co-Section Head of Developmental and Behavioral Pediatrics.
Her research interests are in Fragile X Syndrome, Fetal Alcohol Syndrome, organic causes of ADHD and behavioral phenotypes.
Copyright 2012 Randi Hagerman, M.D., All Rights Reserved

Fifth Disease (Erythema Infectiosum)

What is Fifth Disease?
What causes Fifth Disease?
Who gets Fifth Disease?
How does parvovirus B-19 cause disease?
What are the common findings?
How is Fifth Disease diagnosed?
How is Fifth Disease treated?
What are the complications?
How can Fifth Disease be prevented?
What research is being done?

by Hal B. Jenson, M.D. Chief, Pediatric Infectious Diseases University of Texas Health Science Center San Antonio, TX and by Charles T. Leach, M.D. Associate Professor of Pediatrics University of Texas Health Science Center San Antonio, TX
What is Fifth Disease?
Fifth Disease, also known as “erythema infectiosum,” is a mild, self-limited viral infection. It most commonly occurs in children, and is characterized primarily by fever and a distinctive rash, usually over the cheeks. This distinctive rash is responsible for another name occasionally used for this disease, “slapped-cheek disease.”

What causes Fifth Disease?
Fifth Disease is caused by human parvovirus B19, a DNA virus in the parvovirus family of viruses. This is the only virus in this family that causes disease in humans.

Who gets Fifth Disease?
Parvovirus B19 predominantly infects school children. Children generally acquire an infection during the school months, until May and June. Epidemics occur approximately every six years, and last approximately three years.

How does parvovirus B-19 cause disease?
Parvovirus B19 is transmitted from person-to-person by direct contact or by contaminated secretions of the nose and the mouth. Parvovirus B19 infects the lining of the nose and the upper respiratory tract. Then, it is spread through the blood throughout the body, which causes the rash. The virus also infects the bone marrow cells that are responsible for producing new red blood cells. This particular characteristic may result in complications in those persons who have an underlying anemia or other blood disorder.

What are the common findings?
Fifth Disease can be divided into four phases: 1) the incubation phase, 2) the prodromal phase, 3) the rash phase, and 4) the recovery phase. The incubation phase typically lasts 8 to 12 days after exposure to the virus and does not have any symptoms. During the prodromal phase, the symptoms are mild and include a headache, a low-grade fever, fatigue, and a sore throat. These symptoms usually last for a few days and then resolve. The rash that develops produces an intense rose-red color on both cheeks that does not involve the area around the mouth. This rash is often referred to as the “slapped cheek” rash because of its appearance. The rash usually lasts one to four days and then fades. On other parts of the body, a less prominent rash can occur at the same time or within one to two days. The chest, arms, and legs can develop a flat red rash that has a lace-like appearance.
Adults who get a parvovirus B19 infection are more likely than children to develop joint aches and pains. This typically develops at the time that the rash appears. The joint symptoms usually resolve within four months, but they may persist for a year or more.

How is Fifth Disease diagnosed?
The infection is usually diagnosed by the characteristic appearance of the rash in a child with a fever and no other symptoms. A blood test is available to confirm the infection; however, it usually is not necessary.

How is Fifth Disease treated?
Specific treatment for Fifth Disease is not available. Antibiotics are not helpful because a virus causes Fifth Disease. Viruses cannot be treated with antibiotics. Fever and pain should be treated with acetaminophen or ibuprofen. The disease is usually mild with complete recovery.
Patients with underlying anemia may require a blood transfusion during the acute illness, but they then recover to their previous state of health.

What are the complications?
Children who have underlying anemia are at risk for developing worse anemia with the parvovirus B19 infection. The virus infects the blood cells that produce red blood cells and causes a temporary decrease in the production of red blood cells. Some children require one or, occasionally, more transfusions. Usually, there is recovery within one to two weeks, with a return to normal blood counts within three to four weeks.
The parvovirus B19 infection in pregnant women can result in transmission of the virus to the fetus, and the bone marrow cells of the fetus are infected. This results in anemia in the fetus and leads to the condition known as “hydrops fetalis,” which is associated with fetal heart failure and may cause fetal death and spontaneous abortion. However, even if a woman acquires the parvovirus B19 infection during pregnancy, chances for fetal survival are probably 90%. The virus does not cause birth defects or other problems if the fetus survives the period of the maternal infection.

How can Fifth Disease be prevented?
A vaccine is not available for the human parvovirus B19 infection. Because of the widespread nature of the virus, there is no way to eliminate the risk of exposure. Healthy children with Fifth Disease can attend day care or school because they are most contagious before the rash, and are unlikely to be contagious after the onset of the rash.
Routine exclusion of pregnant women from the workplace or social events is not recommended. Pregnant women who find that they have been in close contact with children in the few days before the onset of the rash of Fifth Disease, or of children who had anemia from Fifth Disease, are at a low risk of infection and complications. Blood tests and fetal ultrasound can help assess the possibility of infection of the fetus.

What research is being done?
Substantial research is currently being performed to develop a vaccine to prevent the human parvovirus B19 infection. If proved to be safe and effective, a vaccine could be administered to children early in life to prevent infection during childhood. The vaccine also could be administered during pregnancy to prevent the occasional fetal death that occurs from the parvovirus B19 infection.

About the Authors
Hal Jenson, M.D.
Dr. Jenson graduated from George Washington University School of Medicine in Washington, DC,
He also completed a residency in pediatrics at the Rainbow Babies and Children’s Hospital of Case Western Reserve University in Cleveland, Ohio, and a fellowship in pediatric infectious diseases and epidemiology at Yale University School of Medicine.
Dr. Jenson has an active research program on the biology of Epstein-Barr virus and other human and non-human primate herpes viruses.
He is active in the general pediatric and infectious diseases teaching and clinical activities of his Department and Division, is a co-editor of Nelson Textbook of Pediatrics and of Pediatric Infectious Diseases: Principles and Practice, and authors the book Pocket Guide to Vaccination and Prophylaxis.
Charles T. Leach, M.D.
Dr. Leach received his medical degree at the University of Utah School of Medicine and completed his pediatrics residency as well as a fellowship in pediatric infectious diseases at UCLA.
He is currently Associate Professor and Director of Research in the Department of Pediatrics at the University of Texas Health Science Center at San Antonio.
Dr. Leach conducts scientific research in the areas of herpes virus infections, pediatric AIDS, and infectious diseases among residents of the Texas-Mexico border.
Copyright 2012 Hal B. Jenson, M.D., All Rights Reserved

FLU

http://www.flu.gov

Food Born Illness

http://www.cdc.gov/foodcore/index.html

Fragile X Syndrome

What is fragile X syndrome?
What causes fragile X syndrome?
Who gets fragile X syndrome?
How does a FMR1 mutation cause disease?
What are the common findings?
How is fragile X syndrome diagnosed?
How is fragile X syndrome treated?
What are the complications?
How is fragile X syndrome prevented?
What research is being done?
Links to additional information
Reading for families
Reading for children

by Randi Hagerman, M.D. Professor of Pediatrics, University of Colorado Health Sciences Center and The Children’s Hospital Denver, Colorado
What is fragile X syndrome?
Fragile X syndrome, also known as FXS, is a genetic disorder, which causes a wide range of problems, from learning disabilities or attention deficits to more significant developmental delays or mental retardation. Fragile X syndrome also can cause significant emotional or behavioral problems, including anxiety, panic attacks, and hyperactivity or Attention Deficit Hyperactivity Disorder (ADHD). Fragile X syndrome is the most common cause of inherited mental retardation.

What causes fragile X syndrome?
Fragile X syndrome is caused by a mutation in the Fragile X Mental Retardation 1 gene (FMR1), which is located on the bottom end of the X chromosome. The FMR1 gene produces a protein that is important for normal brain development. In studies, where the X chromosome is viewed under the microscope, it narrows at the site of the mutation. This narrowing makes the X chromosome look fragile, as if it would break, hence the name, fragile X syndrome.
The mutation is made up of a repeat of the DNA nucleotide code, CGG. If you think of DNA as a twisted ladder, the nucleotides represent the rungs on the ladder, and, at the FMR1 gene, one side of the ladder has the repetitive CGG sequence. In normal individuals, there are approximately 5 to 50 CGG repeats. In individuals who are carriers of fragile X syndrome, but, usually, are not intellectually affected, the CGG repeat is expanded from approximately 50 to 200 repeats. In individuals who are significantly affected by fragile X syndrome, the CGG repetitions expand to greater than 200, and, sometimes, up to 2,000. This is called the full mutation.
The full mutation undergoes a process of methylation, whereby a methyl group (CH3) is placed on the backbone of the DNA, and the gene is “turned off.” Because the gene is turned off, the protein it usually makes is not made. It is the absence-or a deficiency-of the FMR1 protein that causes fragile X syndrome. Some individuals may have cells with the premutation (50 to 200 CGG repeats) and other cells with the full mutation (greater than 200 CGG repeats), so they produce a limited amount of protein, and may be less affected than those individuals who have a full mutation.

Who gets fragile X syndrome?
Boys are more often affected by fragile X syndrome, because they have only one X chromosome. Their other sex chromosome is Y, which makes them male. If they have a full mutation on their X chromosome, they will be significantly affected by fragile X syndrome. Girls, on the other hand, have two X chromosomes. If a full mutation occurs on only one of them, then their other X chromosome will produce some FMR1 protein, if not a full amount. Thus, they will be less affected, as compared to males. Usually, girls with the full mutation have learning disabilities or attention deficit problems; although, in approximately 70% of cases, their IQ will be either in the borderline range (70 to 85) or in the mildly retarded range (50 to 69).
Both males and females can be carriers of this disorder with the premutation. A CGG expansion to the full mutation only occurs when a woman passes on this mutation to the next generation. Therefore, all children who are affected with fragile X syndrome have a mother who is a carrier. Because she has two X chromosomes (one normal and one premutation), the carrier mother has a 50% chance of passing on the mutation to each of her children. Fragile X syndrome usually affects multiple individuals in a family tree; therefore, genetic counseling is important. A genetic counselor will review the problems of all individuals in an extended family, and will talk with family members who are at risk of being a carrier or affected by this disorder.

How does a FMR1 mutation cause disease?
The FMR1 mutation causes disease because the CGG expansion in the full mutation range will turn off the gene, which, in turn, prevents the production of the FMR1 protein. The FMR1 protein controls the production of many other messages made by cells in the central nervous system. The FMR1 protein is thought to be important in determining that proper connections are made between nerve cells in early development.

What are the common findings?
Most children with fragile X syndrome have language delays, i.e., they may not speak in phrases or sentences by 2 or 2 years of age. They also may be hyperactive, inattentive, or impulsive early in childhood, which can lead to a diagnosis of ADHD. Children with FXS are usually extra sensitive to stimuli in their environment, and they frequently have tantrums or emotional outbursts in crowded situations or when making a transition between activities. Shyness or social anxiety may be a common problem; however, initially, many individuals may be shy, and, subsequently, they become impulsive or talkative in social interactions.
Most children with FXS have changes in their connective tissue, such as soft skin, “double-jointed” fingers and thumbs, prominent ears, or a long face. Large testicles are commonly seen in boys with fragile X syndrome; however, this only begins to occur in adolescence or just before the onset of puberty.
Many children may be diagnosed with autistic-like features, such as hand flapping, hand biting, poor eye contact, repetitive speech, and sensitivity to being touched. Approximately 15% of children with FXS also have a diagnosis of autism. These children have more significant social deficits, in addition to shyness. However, most individuals affected by FXS are interested in social interactions and are quite friendly.
Medical problems commonly associated with FXS include recurrent ear infections, perhaps, because of looseness in the connective tissue. This problem is seen in over 60% of cases, and often leads to the placement of pressure equalizing tubes in the eardrums. Rarely, individuals with FXS may have hernias or joint dislocations. Recurrent vomiting is a common problem at the time of birth, and, occasionally, may persist into childhood. Seizures may occur in approximately 20% of patients. Typically, seizures start in early childhood, are usually easily controlled with medication, and often disappear by adolescence or adulthood. Eye problems may be seen in up to 50% of children, including a lazy eye or a need for glasses.

How is fragile X syndrome diagnosed?
Fragile X syndrome can be diagnosed by two methods; both involve a blood test. The first method is called cytogenetic testing. The white blood cells are grown in a lab to show the fragile site on the bottom end of the X chromosome. Not every individual affected by FXS will show the fragile site on the X chromosome. The second method is called FMR1 DNA testing. This method costs approximately $200, which is less expensive than cytogenetic testing. DNA testing will demonstrate the CGG repeat number at the FMR1 gene. This test will diagnose all individuals affected by fragile X syndrome. It also will identify those individuals who are carriers, which cytogenetic testing does not. DNA testing is the best method of diagnosis. Your doctor can order DNA testing or cytogenetic testing on your child, but all individuals who are suspected of having the Fragile X chromosome should have a DNA test, even if cytogenetic testing was previously performed. Rarely, an individual who is positive on cytogenetic testing may be negative on DNA testing, meaning they do not have a mutation at the FMR1 gene.

How is fragile X syndrome treated?
All individuals who are affected by FXS require speech and language therapy and occupational therapy, usually with a sensory integration approach. These therapies stimulate and improve motor and language development. In children who have more severe motor problems, treatment by a physical therapist also is necessary.
Most children affected by FXS also will require special education support in school, including individual and/or group tutoring to help academic progress. Children with FXS often have difficulty with math and, sometimes, spelling and reading. Most children can be mainstreamed into a regular classroom; however, they may require an aide to modify regular classroom assignments and to help them complete work.
Medications can be helpful for treating behavior and emotional problems. The use of stimulant medication, such as methylphenidate (Ritalin) and dextroamphetamine (Dexedrine or Adderall), are helpful for the majority of children with FXS who have significant hyperactivity, short attention spans, or impulsive behavior. Usually, these medications are tried at 5 years of age or older; although, occasionally, they can be helpful in the preschool period. Clonidine or guanfacine (Tenex) are medications that can reduce hyperactivity or overstimulation and improve tantrum behavior. These medications can be used after age 3 and, sometimes, can be combined with stimulant medication. The Selective Serotonin Reuptake Inhibitors (SSRIs), such as Prozac, Zoloft, Paxil, or Luvox, can be helpful in treating anxiety, panic attacks, obsessive compulsive behavior, or aggression and outburst behavior. These medications can be used in childhood, adolescence, or adulthood. Sometimes, severe behavioral problems may require the use of an atypical anti-psychotic drug, such as risperidone; however, such a drug should be used in low doses, when necessary.
Medical therapy includes treating associated problems, such as recurrent ear infections. These require the use of either preventive antibiotics or pressure equalizing tubes to ensure that hearing is normalized and not damaged by continued infections. All children with FXS should be seen by an eye doctor to rule out the possibility of a weak eye muscle or the need for glasses, which occurs in approximately 30% to 50% of cases. If orthopedic problems occur, such as recurrent joint dislocations or severe flat feet, an orthopedist should be seen. Severe flat feet may require the use of a shoe insert or high shoes with a firm arch to provide appropriate support for the foot. Rarely, joint problems may require surgery.
A treatment program should include genetic counseling where parents can review the family tree and determine who is at risk for being a carrier or being affected with FXS. Siblings of a child with FXS should be tested for it with FMR1 DNA testing. Genetic counseling is available to guide prenatal diagnostic procedures, which can identify the degree of the mutation of the fetus at approximately 10 to 15 weeks of pregnancy. Approximately 1 in 200 women in the general population is a carrier of FXS, and approximately 1 in 2,000 women is affected by FXS.

What are the complications?
The complications of treating FXS include side effects from the medications that are used. Higher doses of stimulant medication can cause weight loss, sleep disturbances, or high blood pressure. Children who are treated with medications should see their physicians at least 2 to 3 times per year to follow growth parameters and blood pressure. Medications, such as clonidine or guanfacine, can cause significant sedation, and also may require an EKG. The SSRIs can cause gastrointestinal disturbances or diarrhea, which can be improved by adjusting the dosage or changing to a different medication. Careful follow-up with us about side effects can lead to medication changes and improved symptoms.

How is fragile X syndrome prevented?
It is possible to perform prenatal diagnostic testing for FXS using the FMR1 DNA test. If the fetus is positive for the full mutation, the parents can elect to terminate the pregnancy. Such decisions regarding termination or carrying on a pregnancy with a fetus affected with FXS are very personal decisions. The family must make the decision that is right for them. The genetic counselor and the physician will be supportive of the family’s decision.

What research is being done?
A variety of research projects on fragile X syndrome are being conducted throughout the world. A “knockout mouse model” has been developed where the FMR1 gene is missing. These mice tend to be hyperactive and somewhat learning disabled on psychological tasks. They also have large testicles and changes in their brain, which appear to be similar to humans affected with FXS. The knockout mouse model may be helpful for gene therapy research, where the gene is either replaced or protein is given to the animal to relieve the symptoms. Research also is being conducted on how to “turn on” the gene to produce the FMR1 protein in the nerve cells of FXS patients. Gene replacement therapy or therapy to turn on the gene has not occurred in humans, but it is occurring in test tubes and in animal models.
In addition, research is being performed to determine the best treatments, including medication and educational and/or computer technology, to improve learning in those individuals affected with FXS.

Links to additional information
The National Fragile X Foundation
P.O. Box 190488
San Francisco, CA 94119-0488
Phone: (800) 688-8765
E-mail: natlfx@sprintmail.com
Web: www.fragilex.org
FRAXA Research Foundation
P.O. Box 935
West Newbury, MA 01985-0935
Phone: (978) 462-1866
E-mail: info@fraxa.org
Web: www.fraxa.org

Reading for families
Fragile, Handle With Care: Understanding Fragile X Syndrome. Braden, M. (1997) Chapel Hill: Avanta Publishing. (Can be obtained from The National Fragile X Foundation.)
Fragile X Syndrome: Diagnosis, Treatment and Research, 2nd edition. Hagerman, R.J. and Cronister, A. (eds) (1996) Baltimore: The Johns Hopkins University Press.
Fragile X Syndrome. Hagerman, R.J. (1999) In: “Neurodevelopmental Disorders: Diagnosis and Treatment.” New York: Oxford University Press, 61-132.
A Parent’s Guide to Drug Treatment of Fragile X Syndrome. Tranfaglia, M.R. (1996) FRAXA Research Foundation, West Newbury, MA.
Transitioning “Special” Children Into Elementary School. Weber, J.D. Books Beyond Borders, Inc., 1881 4th Street, #108, Boulder, CO 80302 (1-800-347-6440).

Reading for children
Boys With Fragile X Syndrome. O’Connor, R. (1995). (Can be obtained from the National Fragile X Foundation.)
My Brother Has Fragile X Syndrome. Steiger, C. (1998) Chapel Hill: Avanta Publishing.
(Can be obtained by calling 1-800-434-0322.)

F

Febrile Seizure

Fetal Alcohol Syndrome

Fifth Disease (Erythema Infectiosum)

FLU

Food Born Illness

Fragile X Syndrome

Calvary Pediatrics

Sunshine Pediatrics