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Rett, William's, Angelman's, Fragile X Syndromes, Cornelia de Lange Syndrome Genetic Disorders Rett Syndrome Fact Sheet Request free mailed brochure
http://www.ninds.nih.gov/health_and_medical/pubs/rett.htm Prepared by:
Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892
What is Rett syndrome? What are the stages of the disorder? What causes Rett syndrome? Is Rett syndrome inherited? Who gets Rett syndrome? How is Rett syndrome diagnosed? Why are some cases more severe than others? Is treatment available? What is the outlook for those with Rett syndrome? What research is being done? Where can I find more information?
Rett syndrome is a childhood neurodevelopmental disorder characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures, and mental retardation. It affects females almost exclusively. The disorder was identified by Dr. Andreas Rett, an Austrian physician who first described it in a journal article in 1966. It was not until after a second article about the disorder was published in 1983 that the disorder was generally recognized.updated 7/04 The course of Rett syndrome, including the age of onset and the severity of symptoms, varies from child to child. Before the symptoms begin, however, the child appears to grow and develop normally. Then, gradually, mental and physical symptoms appear. Hypotonia (loss of muscle tone) is usually the first symptom. As the syndrome progresses, the child loses purposeful use of her hands and the ability to speak. Other early symptoms may include problems crawling or walking and diminished eye contact. The loss of functional use of the hands is followed by compulsive hand movements such as wringing and washing. The onset of this period of regression is sometimes sudden. Another symptom, apraxia — the inability to perform motor functions — is perhaps the most severely disabling feature of Rett syndrome, interfering with every body movement, including eye gaze and speech. Individuals with Rett syndrome often exhibit autistic-like behaviors in the early stages. Other symptoms may include toe walking; sleep problems; wide-based gait; teeth grinding and difficulty chewing; slowed growth; seizures; cognitive disabilities; and breathing difficulties while awake such as hyperventilation, apnea (breath holding), and air swallowing. There are four stages of Rett syndrome. Stage I, called early onset, generally begins between 6 and 18 months of age. Quite frequently, this stage is overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first. The infant may begin to show less eye contact and have reduced interest in toys. There may be delays in gross motor skills such as sitting or crawling. Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can persist for more than a year. Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may last for weeks or months. This stage may have either a rapid or a gradual onset as purposeful hand skills and spoken language are lost. The characteristic hand movements begin to emerge during this stage and often include wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth. Hands are sometimes clasped behind the back or held at the sides, with random touching, grasping, and releasing. The movements persist while the child is awake but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing is usually normal during sleep. Some girls also display autistic-like symptoms such as loss of social interaction and communication. General irritability and sleep irregularities may be seen. Gait patterns are unsteady and initiating motor movements can be difficult. Slowing of head growth is usually noticed during this stage. Stage III, also called the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this stage. However, there may be improvement in behavior, with less irritability, crying, and autistic-like features. An individual in stage III may show more interest in her surroundings, and her alertness, attention span, and communication skills may improve. Many girls remain in this stage for most of their lives. The last stage, stage IV — called the late motor deterioration stage — can last for years or decades and is characterized by reduced mobility. Muscle weakness, rigidity (stiffness), spasticity, dystonia (increased muscle tone with abnormal posturing of extremity or trunk), and scoliosis (curvature of the spine) are other prominent features. Girls who were previously able to walk may stop walking. Generally, there is no decline in cognition, communication, or hand skills in stage IV. Repetitive hand movements may decrease, and eye gaze usually improves. Rett syndrome is caused by mutations (structural alterations or defects) in the MECP2 (pronounced meck-pea-two) gene, which is found on the X chromosome (see section on "Who gets Rett syndrome" for a discussion of the importance of the involvement of the X chromosome). Scientists identified the gene — which is believed to control the functions of several other genes — in 1999. The MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which acts as one of the many biochemical switches that tell other genes when to turn off and stop producing their own unique proteins. Because the MECP2 gene does not function properly in those with Rett syndrome, insufficient amounts or structurally abnormal forms of the protein are formed. The absence or malfunction of the protein is thought to cause other genes to be abnormally expressed, but this hypothesis has not yet been confirmed. Seventy to 80 percent of girls given a diagnosis of Rett syndrome have the MECP2 genetic mutation detected by current diagnostic techniques. Scientists believe the remaining 20 to 30 percent of cases may be caused by partial gene deletions, by mutations in other parts of the gene, or by genes that have not yet been identified; thus, they continue to search for other mutations. Although Rett syndrome is a genetic disorder — resulting from a faulty gene or genes — less than 1 percent of recorded cases are inherited or passed from one generation to the next. Most cases are sporadic, which means the mutation occurs randomly, mostly during spermatogenesis, and is not inherited. Rett syndrome affects one in every 10,000 to 15,000 live female births. It occurs in all racial and ethnic groups worldwide. Prenatal testing is available for families with an affected daughter who has an identified MECP2 mutation. Since the disorder occurs spontaneously in most affected individuals, however, the risk of a family having a second child with the disorder is less than 1 percent. Genetic testing is also available for sisters of girls with Rett syndrome and an identified MECP2 mutation to determine if they are asymptomatic carriers of the disorder, which is an extremely rare possibility. Girls have two X chromosomes, but only one is active in any given cell. This means that in a child with Rett syndrome only about half the cells in the nervous system will use the defective gene. Some of the child's brain cells use the healthy gene and express normal amounts of the proteins. The story is different for boys who have an MECP2 mutation known to cause Rett syndrome in girls. Because boys have only one X chromosome they lack a back-up copy that could compensate for the defective one, and they have no protection from the harmful effects of the disorder. Boys with such a defect die shortly after birth. Different types of mutations in the MECP2 gene can cause mental retardation in boys. Doctors diagnose Rett syndrome by observing signs and symptoms during the child's early growth and development, and conducting ongoing evaluations of the child's physical and neurological status. Recently, scientists developed a genetic test to confirm the clinical diagnosis of this disorder; the test involves searching for the MECP2 mutation on the child's X chromosome. Given what we know about the genes involved in Rett syndrome, such tests are able to confirm a clinical diagnosis in up to 80 percent of all cases. Some children who have Rett syndrome-like characteristics or MECP2 genetic mutations do not fulfill the diagnostic criteria for the syndrome as defined below. These persons are described as having "atypical" or "variant" Rett syndrome. Atypical cases account for about 15 percent of the total number of diagnosed cases. A pediatric neurologist or developmental pediatrician should be consulted to confirm the clinical diagnosis of Rett syndrome. The physician will use a highly specific set of guidelines that are divided into three types of clinical criteria: essential, supportive, and exclusion. The presence of any of the exclusion criteria negates a diagnosis of "classic" or "typical" Rett syndrome. Examples of essential diagnostic criteria or symptoms include having apparently normal development until between the ages of 6 and 18 months and having normal head circumference at birth followed by a slowing of the rate of head growth with age (between 3 months and 4 years). Other essential diagnostic criteria include severely impaired expressive language, repetitive hand movements, shaking of the torso, and toe-walking or an unsteady, wide-based, stiff-legged gait. Supportive criteria are not required for a diagnosis of Rett syndrome but may occur in some patients. In addition, these symptoms — which vary in severity from child to child — may not be observed in very young girls but may develop with age. A child with supportive criteria but none of the essential criteria does not have Rett syndrome. Supportive criteria include breathing difficulties; electroencephalogram (EEG) abnormalities; seizures; muscle rigidity, spasticity, and/or joint contracture which worsen with age; scoliosis; teeth-grinding; small feet in relation to height; growth retardation; decreased body fat and muscle mass (although there may be a tendency toward obesity in some affected adults); abnormal sleep patterns, irritability, or agitation; chewing and/or swallowing difficulties; poor circulation of the lower extremities with cold and bluish-red feet and legs; decreased mobility with age; and constipation. In addition to the essential diagnostic criteria, a number of specific conditions enable physicians to rule out a diagnosis of Rett syndrome. These are referred to as exclusion criteria. Children with any one of the following criteria do not have Rett syndrome: enlargement of body organs or other signs of storage disease, vision loss due to retinal disorder or optic atrophy, microcephaly at birth, an identifiable metabolic disorder or other inherited degenerative disorder, an acquired neurological disorder resulting from severe infection or head trauma, evidence of growth retardation in utero, or evidence of brain damage acquired after birth. The course and severity of Rett syndrome vary from individual to individual. Some girls have symptoms from birth onward, while others may have late regression or milder symptoms. Because females have two copies of the X chromosome and need only one working copy for genetic information, they turn off the extra X chromosome in a process called X inactivation. This process occurs randomly so that each cell is left with one active X chromosome. The severity of Rett syndrome in girls is in part a function of the percentage of cells with a normal copy of the MECP2 gene after X inactivation takes place: if X inactivation turns off the X chromosome that is carrying the defective gene in a large proportion of cells, the symptoms will be mild, but if a larger percentage of cells have the X chromosome with the normal MECP2 gene turned off, onset of the disorder may occur earlier and the symptoms may be more severe. There is no cure for Rett syndrome. Treatment for the disorder is symptomatic — focusing on the management of symptoms — and supportive, requiring a multidisciplinary approach. Medication may be needed for breathing irregularities and motor difficulties, and antiepileptic drugs may be used to control seizures. There should be regular monitoring for scoliosis and possible heart abnormalities. Occupational therapy (in which therapists help children develop skills needed for performing self-directed activities — occupations — such as dressing, feeding, and practicing arts and crafts), physiotherapy, and hydrotherapy may prolong mobility. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight. Special academic, social, vocational, and support services may also be required in some cases. Despite the difficulties with symptoms, most individuals with Rett syndrome continue to live well into middle age and beyond. Because the disorder is rare, very little is known about long-term prognosis and life expectancy. While it is estimated that there are many middle-aged women (in their 40s and 50s) with the disorder, not enough women have been studied to make reliable estimates about life expectancy beyond age 40. Within the Federal Government, the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD), two of the National Institutes of Health (NIH), support clinical and basic research on Rett syndrome. Understanding the cause of this disorder is necessary for developing new therapies to manage specific symptoms, as well as for providing better methods of diagnosis. The discovery of the Rett syndrome gene in 1999 provides a basis for further genetic studies and enables the use of recently developed animal models such as transgenic mice. One NINDS-supported study is looking for mutations in the MECP2 gene of individuals with Rett syndrome to find out how the MeCP2 protein functions. Information from this study will increase understanding of the disorder and may lead to new therapies. Scientists know that lack of a properly functioning MeCP2 protein disturbs the function of mature brain cells but they do not know the exact mechanisms by which this happens. Investigators are also trying to find other genetic mutations that can cause Rett syndrome and other genetic switches that operate in a similar way to the MeCP2 protein. Once they discover how the protein works and locate similar switches, they may be able to devise therapies that can substitute for the malfunctioning switch. Another outcome might involve manipulating other biochemical pathways to compensate for the malfunctioning MECP2 gene, thus preventing progression of the disorder. Private, voluntary organizations that offer information and services to those affected by Rett syndrome include the following: International Rett Syndrome Association (IRSA)
9121 Piscataway Road
Suite 2B
Clinton, MD 20735
irsa@rettsyndrome.org
http://www.rettsyndrome.org
Tel: 301-856-3334 800-818-RETT (7388)
Fax: 301-856-3336
Rett Syndrome Research Foundation (RSRF)
4600 Devitt Drive
Cincinnati, OH 45246
monica@rsrf.org
http://www.rsrf.org
Tel: 513-874-3020
Fax: 513-874-2520
Easter Seals
230 West Monroe Street
Suite 1800
Chicago, IL 60606-4802
info@easter-seals.org
http://www.easter-seals.org
Tel: 312-726-6200 800-221-6827
Fax: 312-726-1494
In addition to the NINDS, the following institute within the National Institutes of Health supports research on Rett syndrome: National Institute of Child Health and Human Development (NICHD)
National Institutes of Health, DHHS
31 Center Drive, Rm. 2A32 MSC 2425
Bethesda, MD 20892-2425
http://www.nichd.nih.gov
Tel: 301-496-5133
Fax: 301-496-7101
For information on other neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at: BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
www.ninds.nih.gov 1Rett A. On an unusual brain atropic syndrome with hyperammonemia in childhood. Wien Med Wochenschr 1966; 116:723-726. 2Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann Neurol 1983; 14:471-479. NIH Publication No. 04-4863
December 2003 Prepared by:
Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892
NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history. All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.
William's Syndrome Written by Stephen M. Edelson, Ph.D.
Center for the Study of Autism, Salem, Oregon page updated 7/8/04 Williams Syndrome is a genetic disorder characterized by mild mental retardation. It is a rare disorder in which a portion of DNA material on chromosome 7 is missing. The prevalence in the population is somewhere between 1 out of 20,000 to 50,000 births. Many people with Williams Syndrome exhibit autistic behaviors. This includes: developmental and language delays, problems in gross motor skills, hypersensitivity to sounds, being picky eaters, and perseverating. These individuals differ from the typical autistic individual because they also have cardiovascular abnormalities, high blood pressure, elevated calcium levels, and are very sociable. They also have unique pixie-like facial features--almond shaped eyes, oval ears, full lips, small chins, narrow faces, and broad mouths. - If you would like more information, contact:
- Williams Syndrome Association
P.O. Box 17873
San Diego, CA 92177-8373
©1995, Copyright information
NINDS Williams Syndrome
Reviewed 07-01-2001 Get Web page suited for printing
Email this to a friend or colleague Table of Contents (click to jump to sections) What is Williams Syndrome?
Is there any treatment?
What is the prognosis?
What research is being done?
Organizations
What is Williams Syndrome?
Williams syndrome is a rare, congenital (present at birth) disorder characterized by physical and developmental problems including an impulsive and outgoing (excessively social) personality, limited spatial skills and motor control, and intellectual disability (i.e., developmental delay, learning disabilities, mental retardation, or attention deficit disorder). Other features include characteristic "elfin-like" facial features, heart and blood vessel problems, hypercalcemia (elevated blood calcium levels), low birth weight, slow weight gain, feeding problems, irritability during infancy, dental and kidney abnormalities, hyperacusis (sensitive hearing), and musculoskeletal problems. Symptoms vary among patients. Although individuals with Williams syndrome may show competence in areas such as language, music, and interpersonal relations, their IQs are usually below average, and they are considered moderately to mildly retarded. Scientists have learned that most individuals with Williams syndrome have a deletion of genetic material on chromosome 7. This probably causes the physical and developmental problems experienced by patients. Is there any treatment?
There is neither a cure for Williams syndrome nor a standard course of treatment. Treatment is symptomatic and supportive. Individuals with Williams syndrome need regular monitoring for potential medical problems by a physician familiar with the disorder, as well as specialized services to maximize their potential. What is the prognosis?
The prognosis for individuals with Williams syndrome varies. Some may be able to master self-help skills, complete academic or vocational school, and live in supervised homes or on their own, while others may not progress to this level. What research is being done?
The NINDS supports research on the neurological, behavioral, and genetic components of Williams syndrome. Select this link to view a list of all studies currently seeking patients.
Organizations National Organization for Rare Disorders (NORD)
P.O. Box 1968
(55 Kenosia Avenue)
Danbury, CT 06813-1968
orphan@rarediseases.org
http://www.rarediseases.org
Tel: 203-744-0100 Voice Mail 800-999-NORD (6673)
Fax: 203-798-2291 National Heart, Lung, and Blood Institute (NHBLI)
National Institutes of Health, DHHS
31 Center Drive, Rm. 4A21 MSC 2480
Bethesda, MD 20892-2480
http://www.nhlbi.nih.gov
Tel: 301-592-8573/240-629-3255 (TTY) Recorded Info: 800-575-WELL (-9355) National Institute of Child Health and Human Development (NICHD)
National Institutes of Health, DHHS
31 Center Drive, Rm. 2A32 MSC 2425
Bethesda, MD 20892-2425
http://www.nichd.nih.gov
Tel: 301-496-5133
Fax: 301-496-7101 Williams Syndrome Association
P.O. Box 297
Clawson, MI 48017-0297
info@williams-syndrome.org
http://www.williams-syndrome.org
Tel: 248-244-2229 800-806-1871
Fax: 248-244-2230
NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history. All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.
Provided by:
The National Institute of Neurological Disorders and Stroke
National Institutes of Health
Prader-Willi Syndrome Written by Stephen M. Edelson, Ph.D.
Center for the Study of Autism, Salem, Oregon Prader-Willi Syndrome is a disorder which is sometimes associated with, but not a subtype of, autism. The classical features of this disorder include an obsession with food which is often associated with impulsive eating, compact body build, underdeveloped sexual characteristics, and poor muscle tone. Because of their obsession with food, many people afflicted with Prader-Willi Syndrome are overweight. Most individuals afflicted with Prader-Willi Syndrome have mild mental retardation. Some of the behaviors which are common to both Prader-Willi Syndrome and autism are: delays in language and motor development, learning disabilities, feeding problems in infancy, sleep disturbances, skin picking, temper tantrums, and a high pain threshold. Prader-Willi Syndrome affects approximately 1 in 10,000 people. Most individuals suffering from this disorder are missing a small portion of chromosome 15 which appears to come from the paternal side of the family. When a small portion of chromosome 15 is missing and comes from the maternal side, the person may suffer from Angelman Syndrome. The most effective form of treatment for people suffering from Prader-Willi Syndrome is behavior modification. In general, medications do not appear to very effective for these individuals. For more information about Prader-Willi Syndrome, contact the Prader-Willi Syndrome Association, 2510 S. Brentwood Blvd., Suite 220, St. Louis, MO 63144, telephone: 1- 800-926-4797. In Canada, contact: Ontario Prader-Willi Syndrome Association, 1910 Yonge Street, Fourth Floor, Toronto, Ontario M4S 3B2, Canada, telephone 1-800-563- 1123. ©1995, Copyright information
Landau-Kleffner SyndromeWritten by Stephen M. Edelson, Ph.D.
Center for the Study of Autism, Salem, Oregon Landau-Kleffner Syndrome is manifested as a form of aphasia, (loss of language), which usually develops between 3 and 7 years. It is twice as common in males than females. Initially, these individuals have a healthy, problem-free development with normal speech and vocabulary. These individuals first lose their ability to comprehend (i.e., receptive speech) and then their ability to speak (i.e., expressive speech). These changes can occur gradually or suddenly. People with Landau-Kleffner Syndrome have abnormal EEG patterns (i.e., brain waves) in the temporal lobe (located on the sides of the brain) and in the temporo-parieto-occipital regions during sleep. Diagnosis of this syndrome usually involves examining the person's EEG patterns during sleep. Approximately 70% develop epilepsy; and these seizures are typically infrequent and can be either with or without convulsions. One common characteristic of Landau-Kleffner Syndrome, which is often diagnosed in conjunction with autism, is the failure to respond to sounds. Thus, parents may suspect their child of hearing loss. Autistic characteristics seen in Landau-Kleffner Syndrome individuals include pain insensitivity, aggression, poor eye contact, insistence on sameness, and sleep problems. The cause of Landau-Kleffner Syndrome is not known. Some suggested causes have been a dysfunctional immune system, exposure to a virus, and brain trauma. The prognosis is better when the onset is after age 6 and when speech therapy is started early. Several other treatments have also been shown to be beneficial for many of these individuals, such as anticonvulsant mediations and corticosteroids. There is also a surgical technique in which the pathways of abnormal electrical brain activity are severed. - For additional information, contact:
- C.A.N.D.L.E.
4414 McCampbell
Montgomery, AL 36106.
Fragile X SyndromeWritten by Stephen M. Edelson, Ph.D.
Center for the Study of Autism, Salem, Oregon Fragile X syndrome, called Martin-Bell syndrome, is a genetic disorder and is the most common form of inherited mental retardation. It is a sex-linked genetic abnormality in which a mother is a carrier, transmitting the disorder to her sons. It affects approximately 1 in every 1,000 to 2,000 male individuals, and the female carrier frequency may be substantially higher. Males afflicted with this syndrome typically have a moderate to severe form of intellectual handicap. Females may also be affected but generally have a mild form of impairment. Approximately 15% to 20% of those with Fragile X Syndrome exhibit autistic-type behaviors, such as poor eye contact, hand-flapping or odd gesture movements, hand-biting, and poor sensory skills. Behavior problems and speech/language delay are common features of Fragile X Syndrome. People with Fragile X syndrome also have a number of recognizable physical features, including a high arched palate, strabismus (lazy eye), large ears, long face, large testicles in males, poor muscle tone, flat feet, and sometimes mild, heart valve abnormalities. Although most individuals with Fragile X syndrome have a characteristic 'look' (long face and large ears), there are some who do not have typical features. Many hospitals and laboratories perform blood tests to diagnose Fragile X syndrome. Several treatments are recommended for individuals with this disorder, including mild medications for behavior problems and therapies for speech and language and sensory improvement. Also, families are advised to seek genetic counseling to understand the inheritable nature of Fragile X Syndrome and to discuss with family members the likelihood other individuals or future offspring may have this disorder. - For more information, contact:
- The Fragile X Foundation
P.O. Box 30023
Denver, CO 80203
We would like to thank Dr. Peter Jacky of Kaiser Sunnyside Hospital in Clackamas, Oregon for his comments on this article. The Autism Research Institute distributes an information packet on Fragile X Syndrome.
Click here to learn how to obtain this packet.
Angelman Syndrome Written by Stephen M. Edelson, Ph.D.
Center for the Study of Autism, Salem, Oregon Angelman Syndrome is not considered a subtype of autism, but individuals suffering from this disorder exhibit many behaviors characteristic of autism. They are also sometimes given a secondary diagnosis of autism. In 1965, Harry Angelman, M.D., an English physician, was the first to describe a group of individuals with similar behavioral and physical similarities, which was later termed 'Angelman Syndrome.' For many of these individuals, a small portion of chromosome 15 is missing; and this appears to be from the maternal side. Interestingly, when a small portion of chromosome 15 is missing and is from the paternal side, the child may suffer from Prader-Willi Syndrome. Similar to autism, individuals with Angelman Syndrome display the following behaviors: hand-flapping, little or no speech, attention deficits, hyperactivity, feeding and sleeping problems, and delays in motor development. These individuals may also engage in biting and hair pulling. In contrast to autism, people with Angelman Syndrome are often described as very sociable. They are very affectionate and engage in frequent laughing. The majority of these individuals have abnormal EEG's and epilepsy. Many tend to have a stiff-legged gait and jerky body movements. These individuals also have common facial features, such as a wide smiling mouth, a thin upper lip, and deep set eyes. More than half have low levels of pigmentation in their eyes, hair, and skin. The prevalence rate of Angelman Syndrome is estimated to be 1 in 25,000 individuals, and the majority of these individuals are described as severely mentally retarded. Suggested interventions for Angelman Syndrome include: behavior modification, speech therapy, and occupational therapy. For information about Angelman Syndrome in the United States, contact: Angelman Syndrome Foundation, 3015 E. New York Street, suite A2265, Aurora, IL 60504. Telephone: 800-432-6435; 630-978-4245; Fax: 630-978-7408. Website: www.angelman.org. In Canada, contact: Canadian Angelman Syndrome Society, P.O. Box 37, Priddis, Alberta, TOL 1WO, Canada, telephone: (403) 931-2415.
Autism-Related Disorders in DSM-IV
Meredyth Goldberg Edelson, Ph.D.
Department of Psychology, Willamette University
Salem, Oregon
The new Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) came out in the summer of 1994. There have been numerous changes which affect the diagnoses of Autism and related disorders. This summary will review those changes and the possible impact of these changes on persons with Autism and related disorders.
First, the category of disorders under which Autism falls, Pervasive Developmental Disorders, are now coded in a different location in DSM-IV than in its predecessor, DSM-IIIR. It used to be the case that the Pervasive Developmental Disorders were coded on Axis II, the axis that was reserved for long-term, stable disorders with relatively poor prognosis for improvement. Pervasive Developmental Disorders are now coded on Axis I, the axis that is used to diagnose episodic and more transient clinical disorders. The possible implication of this move is the recognition that symptoms of these disorders can vary and possibly improve with intervention whereas the disorders which remain on Axis II, mental retardation and the personality disorders, are typically long-term and often unresponsive to treatment.
In addition to moving the axis on which these disorders are diagnosed, the diagnostic criteria for Autism has changed slightly, and three Autism-related disorders (which had been recognized in the European community's International Classification of Diseases (ICD) system for awhile) have been added to DSM-IV. In order for a diagnosis of Autism to be made, the person still needs to evidence problems in three broad areas: social interaction, communication, and stereotyped patterns of behavior. However, the number of symptoms which fall under these three broad areas have been reduced from 16 to 12 to make this diagnostic category more homogeneous. The individual needs to evidence 6 symptoms spanning the three broad areas with at least two symptoms indicating social interaction deficits, and one symptom in each of the communication and stereotyped patterns of behavior categories. The symptoms which fall under the social interaction category are: marked impairment in the use of multiple nonverbal behaviors; failure to develop age-appropriate peer relationships; lack of spontaneous seeking to share interests and achievements with others; and lack of social or emotional reciprocity. The symptoms which fall under the communication category are: delay in or lack of spoken language development (with no compensation through alternative modes of communication); in verbal persons, marked impairment in conversational skills; stereotyped and repetitive use of language; and lack of spontaneous age-appropriate make-believe or social imitative play. The symptoms which fall under the stereotyped patterns of behavior category are: preoccupation with at least one stereotyped and restricted patterns of interest to an abnormal degree; inflexible adherence to nonfunctional routines or rituals; stereotyped and repetitive motor mannerisms; and preoccupation with parts of objects. Besides at least 6 of these symptoms, there also needs to be delays in either social interaction, social communication, or symbolic or imaginative play. Another change is that the age of onset of these symptoms has to occur prior to age 3.
A new disorder added to the DSM system is Rett's Disorder. In order for this diagnosis to be made, all of the following need to be present: apparently normal pre- and perinatal development; apparently normal psychomotor development through the first 5 months of life; and normal head circumference at birth. In addition, all of the following symptoms need to occur after a period of normal development: deceleration of head growth between 5-48 months; loss of previously acquired purposeful hand skills between 5-30 months with subsequent stereotyped hand movements (e.g., hand-wringing); loss of social engagement; appearance of poorly coordinated gait; severely impaired expressive and receptive language development; and severe psychomotor retardation. The symptoms of Rett's Disorder are similar to Autism but the prognosis is poorer; and in Autism, the symptoms may or may not have occurred following a period of normal development.
Childhood Disintegrative Disorder is another new diagnosis in DSM-IV. This disorder is also similar to Autism, but there must clearly be evidence of apparently normal development for at least the first 2 years of life (with regard to communication, social relationships, play, and adaptive behavior). This category covers what some professionals refer to as "Regressive Autism" where the individual develops Autistic symptoms much later than a "typical" Autistic child. For a diagnosis of Childhood Disintegrative Disorder to be made, there must be a clinically significant loss of previously acquired skills (before age 10) in at least two areas: expressive or receptive language; social skills or adaptive behavior; bowel or bladder control; play; or motor skills. Additionally, there needs to be abnormalities of functioning in at least two of the following areas: qualitative impairment in social interaction; qualitative impairment in communication; and restricted, repetitive, and stereotyped patterns of behavior. This last criteria is the same as in Autism.
The final new Autism-related disorder added under the Pervasive Developmental Disorders section of DSM-IV is Asperger's Disorder. For this diagnosis to be made, there must be qualitative impairment in social interaction as manifested by at least 2 of the following: marked impairment in the use of multiple nonverbal behaviors (e.g., eye contact, gestures); failure to develop age appropriate peer relationships; lack of spontaneous seeking to share interests, or achievements with others; lack of social or emotional reciprocity; restricted repetitive and stereotyped patterns of behaviors, interests, and activities as manifested by at least 1 of the following: preoccupation with at least one stereotyped and restricted patterns of interest to an abnormal degree; inflexible adherence to nonfunctional routines or rituals; stereotyped and repetitive motor mannerisms; and preoccupation with parts of objects. There must additionally be clinically significant impairment in social, occupational or other functioning; and no clinically significant delay in language, cognitive development, adaptive behavior, or in curiosity about the environment. Asperger's Disorder is the diagnosis which will likely be made for persons who have traditionally been labeled as having "High Functioning Autism." It is the appropriate diagnosis for individuals who have evidence of many Autistic-like symptoms but for whom there are no language impairments.
The reasons for tightening the criteria for Autism and for adding Rett's Disorder, Childhood Disintegrative Disorder, and Asperger's Disorder to DSM-IV is to recognize that Autism is a disorder with many possible symptom variants. Because of this, individuals diagnosed with Autism in the past have been heterogeneous. This has made it difficult to conduct research to determine the etiology, prognosis, and appropriate treatment for individuals with Autism. Hopefully, as the DSM system recognizes the variability of Autistic-like behaviors across individuals, researchers can determine the etiologies and treatments for each of these related disorders. One question that remains unanswered due to this refinement in the DSM system is how the schools will recognize the need for services for individuals in all four of these diagnostic categories, not just for those diagnosed with Autism. Currently under PL 94-142, individuals with Autism must have services provided for them by the schools. However, individuals with Pervasive Developmental Disorder (PDD), the category that used to cover Asperger's Disorder-like symptoms and atypical Autism in DSM-IIIR, often had difficulty receiving services through the schools. Hopefully, the push for more homogeneity in individuals with Autism and Autism-related disorders like Rett's Disorder, Childhood Disintegrative Disorder, and Asperger's Disorder, will not result in some individuals losing out in much needed interventions.
Williams Syndrome Table of Contents (click to jump to sections)What is Williams Syndrome?
Is there any treatment?
What is the prognosis?
What research is being done?
Organizations
What is Williams Syndrome?
Williams syndrome is a rare, congenital (present at birth) disorder characterized by physical and developmental problems including an impulsive and outgoing (excessively social) personality, limited spatial skills and motor control, and intellectual disability (i.e., developmental delay, learning disabilities, mental retardation, or attention deficit disorder). Other features include characteristic "elfin-like" facial features, heart and blood vessel problems, hypercalcemia (elevated blood calcium levels), low birth weight, slow weight gain, feeding problems, irritability during infancy, dental and kidney abnormalities, hyperacusis (sensitive hearing), and musculoskeletal problems. Symptoms vary among patients. Although individuals with Williams syndrome may show competence in areas such as language, music, and interpersonal relations, their IQs are usually below average, and they are considered moderately to mildly retarded. Scientists have learned that most individuals with Williams syndrome have a deletion of genetic material on chromosome 7. This probably causes the physical and developmental problems experienced by patients. Is there any treatment?
There is neither a cure for Williams syndrome nor a standard course of treatment. Treatment is symptomatic and supportive. Individuals with Williams syndrome need regular monitoring for potential medical problems by a physician familiar with the disorder, as well as specialized services to maximize their potential. What is the prognosis?
The prognosis for individuals with Williams syndrome varies. Some may be able to master self-help skills, complete academic or vocational school, and live in supervised homes or on their own, while others may not progress to this level. What research is being done?
The NINDS supports research on the neurological, behavioral, and genetic components of Williams syndrome. Select this link to view a list of all studies currently seeking patients.
National Organization for Rare Disorders (NORD)
P.O. Box 1968
(55 Kenosia Avenue)
Danbury, CT 06813-1968
orphan@rarediseases.org
http://www.rarediseases.org
Tel: 203-744-0100 Voice Mail 800-999-NORD (6673)
Fax: 203-798-2291
National Heart, Lung, and Blood Institute (NHBLI)
National Institutes of Health, DHHS
31 Center Drive, Rm. 4A21 MSC 2480
Bethesda, MD 20892-2480
http://www.nhlbi.nih.gov
Tel: 301-592-8573/240-629-3255 (TTY) Recorded Info: 800-575-WELL (-9355)
National Institute of Child Health and Human Development (NICHD)
National Institutes of Health, DHHS
31 Center Drive, Rm. 2A32 MSC 2425
Bethesda, MD 20892-2425
http://www.nichd.nih.gov
Tel: 301-496-5133
Fax: 301-496-7101
NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history.All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.
Provided by:
The National Institute of Neurological Disorders and Stroke
National Institutes of Health
Syndrome is a medical term for a condition in which there is a collection of signs (observable body changes) and symptoms (problems related by the patient) recognizable by a doctor's exam. Individuals with a syndrome may not have all of its associated signs and symptoms, but they must have enough to be considered "diagnostic." Conversely, because someone may display some of the signs and symptoms of a syndrome, does not necessarily mean they have it. How is Cornelia de Lange Syndrome (CdLS) recognized?
CdLS is a congenital syndrome, meaning it is present from birth. Most of the signs and symptoms may be recognized at birth or shortly thereafter. A child need not demonstrate each and every sign or symptom for the diagnosis to be made. As with other syndromes, individuals with CdLS strongly resemble one another. Common characteristics include: low birthweight (usually, but not always, under five pounds), delayed growth and small stature, and small head size (microcephaly). Typical facial features include thin eyebrows which frequently meet at midline (synophrys), long eyelashes, short upturned nose and thin, downturned lips. Other frequent findings include excessive body hair (hirsutism), small hands and feet, partial joining of the second and third toes, incurved fifth fingers, gastroesophageal reflux, seizures, heart defects, cleft palate, bowel abnormalities, feeding difficulties, and developmental delay. Limb differences, including missing limbs or portions of limbs, usually fingers, hands or forearms, are also found in some individuals. Why is it called Cornelia de Lange Syndrome?
In 1933, Dr. Cornelia de Lange, a Dutch pediatrician, described two children with similar features, one 17 months and the other 6 months, who were admitted within weeks of each other to Emma Children's Hospital.
Cornelia de Lange also known as:
Amsterdam Dwarf Syndrome de Lange
Brachmann-de Lange Syndrome
BDLS
CdLS
de Lange Syndrome
Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth retardation); characteristic abnormalities of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe mental retardation. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); an abnormally long vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares); and a protruding upper jaw (maxillary prognathism). Additional, characteristic facial abnormalities may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck; and abnormally curly, long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, or webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands, and fingers. Infants with Cornelia de Lange syndrome may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched "growling" cry; heart defects; delayed skeletal maturation; hearing loss; or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from case to case. In most individuals with the disorder, Cornelia de Lange syndrome appears to occur randomly for unknown reasons (sporadic). However, there have been some familial cases, suggesting autosomal dominant inheritance. According to investigators, the disorder may be caused by changes (mutations) of a gene or genes on the long arm (q) of chromosome 3 (3q26.3).
The first child had pneumonia. Her first year of life had been characterized by a lot of feeding difficulties and she was very small for her age, with a proportionately smaller head circumference.Other unusual facial characteristics were noted by Dr. de Lange. Soon after this child was discharged, a second little girl was admitted. Not only did they have common medical problems, but their resemblance to each other was remarkable. In each case the doctor described what she observed with great care and detail. Professor de Lange followed her own advice: "Observe closely first." Nowhere was the puzzled physician able to find a similar patient described in medical literature. Cornelia de Lange is now generally credited with describing the collection of symptoms comprising the syndrome that bears her name. The syndrome is sometimes referred to as Brachmann-de-Lange Syndrome after Dr.W. Brachmann, who described a similar patient in 1916. Dr. de Lange may have overlooked his report because he concentrated on characteristics of the upper limbs and wrote on the facial symptoms less specifically. How many people have CdLS?
The exact incidence is unclear, but it is thought to be between 1:10,000 and 1:30,000 live births. For example, this would suggest that a population the size of Canada might experience 18 births per year of children with CdLS, in Ohio one might expect 8, and in the United Kingdom, 38 births a year. Is the life expectancy known?
Not with certainty. Earlier, many children died of serious medical problems in infancy because their needs were not anticipated. This is no longer the case, and it is expected that most will live into adulthood. Is there always mental retardation?
Usually, ranging from mild to profound. The majority fall in the moderate to severe range. What causes CdLS?
At present, the cause is not clearly known, although it is suspected that a gene may be responsible. At present there are several research programs underway which are attempting to find answers to the cause of CdLS. Is CdLS hereditary?
Not in the usual sense of a gene passing directly from parent to child. It is likely that if a gene is involved, it is simply a rare and random mutation. This mutant gene is almost never passed on to the next generation because affected individuals seldom have children of their own. There have been rare instances in which mildly affected individuals have had children with the syndrome. Can CdLS be detected before birth?
Not at present, although there are tests which may help resolve some of the uncertainty felt by CdLS families in future pregnancies. High resolution ultrasound may be useful to monitor for unusually poor fetal growth or detectable limb abnormalities. Genetic counseling centers are able to provide current information on the development of other prenatal tests. How is a diagnosis made?
A thorough medical evaluation including a history and physical examination, family history, laboratory tests, X-rays and chromosome analysis is usually conducted before a diagnosis is made. Since there is no specific test for CdLS, this is best accomplished through a referral to a genetics specialist or clinic. I think my child has CdLS, what can I do?
If you suspect that your child has CdLS, you should arrange for an evaluation by a genetics specialist. Arrangements can usually be made through your local physician, hospital, or university medical center. If my child is diagnosed as having CdLS, what can I expect?
Each child will progress at his/her own rate, but you can generally expect a slower than average rate of development. The area of speech and communication is often delayed, even in the more mildly affected. Infant stimulation programs and other developmental and therapeutic interventions are strongly recommended. Growth and development charts are available through the Foundation.
Note from webmaster of specialneedsnurse.org: There has been reported the discovery of the gene for this disorder click on this link for more information Cornelia de Lange Syndrome Foundation
(as defined by the
NICHD)
McCune-Albright Syndrome Division Introduction The McCune-Albright Syndrome is named for the two physicians who described it over 50 years ago. They reported a group of children, most of them girls, with an unusual pattern of associated abnormalities: bone disease, with fractures, asymmetry and deformity of the legs, arms and skull; endocrine disease, including early puberty with menstrual bleeding, development of breasts and pubic hair and an increased rate of growth; and skin changes, with areas of increased pigment distributed in an asymmetric and irregular pattern. Today, we use the term "McCune-Albright Syndrome" to describe patients who have some or all of these bone, endocrine, and skin abnormalities. In the years since it was first identified, however, we have studied many additional patients, and have learned that the condition has a broad spectrum of severity. Sometimes, children are diagnosed in early infancy with obvious bone disease and markedly increased endocrine secretions from several glands; a very few of these severely affected children have died. At the opposite end of the spectrum, many children are entirely healthy and have a normal life expectancy. They have little or no outward evidence of bone or endocrine involvement, may enter puberty close to normal age, and have no unusual skin pigment at all. Because of this marked variability among some patients, the various components of this complicated syndrome are treated separately in the following sections. ENDOCRINE ABNORMALITIES Precocious Puberty When the signs of puberty (development of breasts, testes, pubic and underarm hair, body odor, menstrual bleeding and increased growth rate) appear before the age of 8 years in a girl and 9 1/2 years in a boy, it is termed 'precocious puberty'. In the most common form of precocious puberty, there is early activation of the regions in the brain which control the maturation of the gonads (ovaries in a girl and testes in a boy). One brain center, the hypothalamus, secretes a substance called gonadotropin-releasing-hormone or GnRH. This acts, in turn, on another part of the brain, the pituitary gland, to cause increased secretion of hormones called gonadotropins (LH and FSH) that travel through the bloodstream, and act on the ovaries or testes to stimulate secretion of estrogen or testosterone. Endocrinologists find out whether a child with precocious puberty has early activation of the hypothalamus and pituitary (gonadotropin-dependent precocious puberty) by measuring the levels of LH and FSH in the blood after an injection of a synthetic preparation of GnRH. After studying many girls with McCune-Albright syndrome, however, we have learned that most do not appear to have early activation of the hypothalamus and pituitary, because their levels of LH and FSH are usually low, or similar to those of prepubertal children. The precocious puberty in McCune-Albright girls is caused by estrogens which are secreted into the bloodstream by ovarian cysts, which enlarge, and then decrease in size over periods of weeks to days. The cysts can be visualized and measured by ultrasonography, in which sound waves are used to outline the dimensions of the ovaries. The cysts may become quite big, occasionally over 50 cc in volume (about the size of a golf ball). Frequently, menstrual bleeding and breast enlargement accompany the growth of a cyst. In fact, menstrual bleeding under 2 years of age has been the first symptom of McCune-Albright syndrome in 85% of patients. Although ovarian cysts and irregular menstrual bleeding may continue into adolescence and adulthood, many adult women with McCune-Albright syndrome are fertile, and can bear normal children. The precocious puberty in McCune-Albright syndrome has been difficult to treat. After surgical removal of the cyst or of the entire affected ovary, cysts usually recur in the remaining ovary. A progesterone-like hormone called Provera can be given to suppress the menstrual bleeding, but does not appear to slow the rapid rates of growth and bone development, and may have unwanted effects on adrenal functioning. The biosynthetic forms of GnRH (Deslorelin, Histerelin, and Lupron) which suppress LH and FSH, and are used to treat the common, gonadotropin-dependent, form of precocious puberty, are not effective in most girls with McCune-Albright syndrome. An investigational form of treatment, using oral medications which block estrogen synthesis, (testolactone and fadrozole) is now being tested in girls with McCune-Albright syndrome, and has been beneficial in many patients. Thyroid Function Almost 50% of patients with McCune-Albright syndrome have thyroid gland abnormalities; these include generalized enlargement called goiter, and irregular masses such as nodules and cysts. Some patients have subtle structural changes detected only by ultrasonography. Pituitary thyroid-stimulating-hormone (TSH) levels are low in these patients, and thyroid hormone levels may be normal or elevated. Therapy with drugs which block thyroid hormone synthesis (Propylthiouracil or Methimazole), can be given if thyroid hormone levels are excessively high. Growth Hormone Excessive secretion of pituitary growth hormone has been seen in a few patients with McCune-Albright syndrome. Most of these have been diagnosed as young adults, when they developed the coarsening of facial features, enlargement of hands and feet, and arthritis characteristic of the condition termed acromegaly. Therapy has included surgical removal of the area of the pituitary which is secreting the hormone, and the use of new, synthetic analogs of the hormone somatostatin, which suppress growth hormone secretion. Other Endocrine Abnormalities Rarely, adrenal enlargement, and excessive secretion of the adrenal hormone cortisol is seen in McCune-Albright syndrome. This may cause obesity of the face and trunk, weight gain, skin fragility and cessation of growth in childhood. These symptoms are called Cushing's Syndrome. Treatment is removal of the affected adrenal glands, or use of drugs which block cortisol synthesis. Some children with McCune-Albright syndrome have very low levels of phosphorus in the blood due to excessive losses of phosphate in the urine. This may cause bone weakening and the condition called rickets. ;It may be treated with oral phosphates and supplemental vitamin D. BONE DISEASE; POLYOSTOTIC FIBROUS DYSPLASIA The term polyostotic fibrous dysplasia means "abnormal fibrous tissue growth in many bones". In affected areas, normal bone is replaced by irregular masses of fibroblast cells. When this occurs in weight-bearing bones, such as the femur (upper leg bone), limping, deformity and fractures may result. In many children, the arms and/or legs are of unequal length, even in the absence of actual fracture. Regions of fibrous dysplasia are also very common in the bones that form the skull and upper jaw. If these areas begin to expand, skull and facial asymmetry may result. Polyostotic fibrous dysplasia can often be seen in a plain X-ray picture of the skeleton. A more sensitive method of finding lesions is a bone scan, in which a small amount of radioactivity (an isotope of technetium) is injected into a vein, taken up by the abnormal tissues, and detected by a scanner. The severity of bone disease in McCune-Albright syndrome is quite variable. Some children may be minimally affected, with no asymmetry, deformity or fracture, and lesions detected only by bone scan. In a few children, lesions are only found in the base of the skull. By repeating bone scans at intervals of one to two years, we have seen that in some children, the bone disease may become more extensive over time. Unfortunately, severe bone disease can have permanent effects upon physical appearance and mobility. There is no known hormonal or medical treatment that has been proven to be effective in controlling progressive polyostotic fibrous dysplasia. Surgical procedures to correct fracture and deformity include grafting, pinning and casting. Skull and jaw changes are often corrected surgically, with great improvement in appearance. SKIN ABNORMALITIES The irregular, flat areas of increased skin pigment in McCune-Albright syndrome are called cafe-au-lait spots because, in children with light complexions, they are the color of coffee with milk. In dark-skinned individuals, these spots may be difficult to see. Most children have the pigment from birth, and it almost never becomes more extensive. The pattern of the pigment distribution is unique, often starting or ending abruptly at the midline on the abdomen in front or at the spine in back. Some children have no cafe-au-lait pigment at all; in a few, it is confined to small areas, such as the nape of the neck or crease of the buttocks. There are seldom any medical problems associated with the areas of cafe-au-lait pigment. Some adolescent children may want to use makeup to obscure areas of dark pigment on the face. RECENT RESEARCH So far, we have not found a cure for the bone and endocrine disease in McCune-Albright syndrome. It cannot yet be diagnosed before birth and we cannot accurately predict how severe the disease may become in an affected child. There are no reported cases of any parent being affected, and the children of women with McCune-Albright syndrome are normal. All races appear to be affected equally. Thus, we are not yet certain of the genetic origin of the defect. It is believed, however, that it may be the result of a mutation occurring early in the development of the embryo. Recently, researchers have discovered abnormal mutations in DNA obtained from the affected ovaries, adrenals and liver of several patients with the McCune-Albright syndrome. The DNA contained the genetic code for one component, called a G protein, of a signalling system which is present in many cells, and which is known to be involved in endocrine cell growth and secretion. The presence of this mutation could result in uncontrolled cell function or hormone secretion. This research is continuing, and it may soon enable us to plan better methods of treatment for patients with the McCune-Albright syndrome.
Achondroplasia Tarda
also known as:
Hypochrondroplasia
Ravenna's Syndrome
Léri’s Hypochondroplasia
Atypichal Achondroplasia Syndrome
(as defined by the
National Organization for Rare Disorders)
PRELIMINARY DRAFT
This preliminary draft has not been approved by our medical advisors; therefore, its accuracy cannot be guaranteed. Verification of medical accuracy is pending. This is the most current information that NORD has available at this time. Hypochrondroplasia is a genetic disorder characterized by small stature and disproportionately short arms, legs, hands, and feet (short-limbed dwarfism). Short stature often is not recognized until early to mid childhood or, in some cases, as late as adulthood. In those with the disorder, bowing of the legs typically develops during early childhood but often improves spontaneously with age. Some affected individuals may also have an abnormally large head (macrocephaly), a relatively prominent forehead, and/or other physical abnormalities associated with the disorder. In addition, in about 10 percent of cases, mild mental retardation may be present. In some cases, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history. In other instances, the disorder is familial with autosomal dominant inheritance.
Crouzon's and Apert's SyndromeOVERVIEW Crouzon and Apert syndromes are the most common of the craniosynostosis syndromes. Craniosynostosis refers to the early closing of one or more of the sutures of an infant's head. The skull is normally composed of bones which are separated by sutures. This diagram shows the different sutures which can be involved.  As an infant's brain grows, open sutures allow the skull to expand and develop a relatively normal head shape. If one or more of the sutures has closed early, it causes the skull to expand in the direction of the open sutures. This can result in an abnormal head shape. In severe cases, this condition can also cause increased pressure on the growing brain.
The coronal suture goes from ear to ear on the top of the head and fusion of both sides ( bicoronal synostosis or brachycephaly) results in a very flat, recessed forehead. This is the suture fusion found most often in Crouzon and Apert Syndromes.  | In addition to craniosynostosis these children also have fusion of the sutures or bones in the cranial base and midface, and shallow eye sockets. This gives the appearance of a flat midface and eyes which protrude. In addition, children with Apert Syndrome have syndactaly (webbing) of the hands and feet. |
Crouzon Syndrome occurs in approximately 1 in 25,000 births. It may be transmitted as an autosomal dominant genetic condition or appear as a fresh mutation ( no affected parents). The appearance of an infant with Crouzons can vary in severity from a mild presentation with subtle midface characteristics to severe forms with multiple cranial sutures fused and marked midface and eye problems. |
The incidence of Apert syndrome is approximately 1 in 100,000 births and most cases are fresh mutations. The general features of a child with Apert syndrome are similar to those in Crouzon syndrome however there is not as much variability between cases and the degree of presentation is more severe. EVALUATION AND TREATMENT As with any craniofacial disorder, treatment by a multidisciplinary team working together with the family provides the best results. In the newborn period some potential problems that may need to be addressed include respiratory difficulties, feeding problems, neurologic complications such as hydrocephalus, and the potential risk of developmental delay. If a cleft palate is present this could cause some feeding difficulty. Techniques described in the section on feeding may be used. (feeding) The infants shallow midface and/or small or partially obstruced nasal passages can cause respiratory problems and also contribute to feeding difficulty. Evaluations by the ENT specialists are important and a tracheostomy may be necessary to relieve the airway problems. In Crouzon and Apert syndromes synostosis of 2 or more cranial sutures may be involved, therefore there can be a risk for increased intracranial pressure. There is also a greater chance of hydrocephalus in these infants than those with single suture fusion and evaluation and close monitoring by the team neurosurgeon is important. The reported incidence of mental retardation in patients with Crouzon syndrome is between 0% and 20% while a higher incidence ( approx. 20-30%) has been reported with Apert syndrome. Referral to an infant stimulation program may be helpful. After the newborn period, the multidisciplinary team continues to evaluate the childs needs. Audiology (hearing test) and speech evaluations are important to insure good speech and language development. Assessment by the opthalmologist is important, especially if the eyelids are not protecting the eyes completely or if there are eye muscle problems. ORTHODONTIC CONCERNS Orthodontic evaluation should begin at age 3-4 in these children. The upper jaw is usually set back and small in all dimensions. This results in severe crowding of the permanent teeth, as well as a significant "underbite", a condition where the top teeth meet inside of the bottom teeth. The palate is constricted and high ( see picture). Delayed dental eruption is common, and extra or missing teeth have been noted on occasion. Treatment requires extraction of some permanent teeth to alleviate the crowding, as well as expansion of the maxilla, either surgically or through the use of orthodontic devices. TREATMENT Treatment in infancy is directed at correction of the suture fusion and resultant misshapen head. ( see section on craniosynostosis ).
Surgical treatment of the midface deformity is usually done during the preschool period ( age 4-6 yrs). Conventional surgical advancement of the midface requires numerous cuts of the facial bones and advancing the midface region to a predetermined level. This usually requires bone grafts. Plates and screws are used to stabilize the new position. The past several years have seen a significant increase in treatment using a technique called Osteogenic Distraction. The same surgical boney cuts are performed and a expansion device is inserted, where by gradual advancement of the midface region can be obtained. Research has indicated this may provide a more stable correction. Return to Contents
(as defined at
http://www.surgery.mc.vanderbilt.edu/surgery/plastic/cfa/crouzon.htm) Crouzon's syndrome is associated with a marked cessation of midfacial growth. Consequently, the middle portion of the child's face does not keep up with the mandible, resulting in very irregular facial characteristics. This can be corrected surgically by advancing the middle portion of the patient's face, thus increasing the ability to occlude the teeth and protect the eyes while giving a more pleasing appearance. If left uncorrected, the eyes become so proptotic that blindness may ensue. Return to Contents
(as defined at
http://www.whonamedit.com/synd.cfm/1382.html) Crouzon's syndrome Synonyms:
Dysostosis craniofacialis
Dysostosis craniofacialis hereditaria
Dysostosis cranio-orbitofacialis.
Associated persons:
Description:
Craniostosis with widening of the skull and high forehead, ocular hypertelorism, exophthalmos, beaked nose, and hypoplasia of the maxilla. Crouzon first described the disturbance in a mother and a son with abnormal facial features presented to the Medical Society of Paris. Three years later he described a second kindred, in which seven persons in successive generations were affected. Inheritance is autosomal dominant. Return to Contents
(as defined at
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10332291&dopt=Abstract&itool=iconabstr) Clinical features of Crouzon's syndrome patients with and without a positive family history of Crouzon's syndrome.
al-Qattan MM, Phillips JH.
Division of Plastic Surgery, Hospital for Sick Children, University of Toronto, Ontario, Canada.
Crouzon's syndrome occurs in 1 in 25,000 live births and follows an autosomal dominant mode of transmission. However, 30 to 60% of cases are sporadic and represent fresh mutations. Previous reports involving large series of Crouzon's syndrome patients mixed sporadic and familial cases. In this article, the clinical features of 17 familial cases of Crouzon's syndrome were compared with another 27 sporadic cases. Furthermore, familial cases were studied to document (1) expressivity in members of the same family; (2) the skull base angle in unoperated members of the same family, and (3) the presence of germinal mosaicism. In familial cases of Crouzon's syndrome, craniosynostosis and proptosis were seen in 76% and 88% of patients, respectively. On the other hand, these two features were observed in 100% of sporadic cases. Variability of expression in members of the same family was a common finding. The cranial base angle was also variable in the affected members of the same family. In the series, germinal mosaicism was suspected in one family. Possible explanations for our findings are discussed as well as the implications of genetic mapping in Crouzon's syndrome.
PMID: 10332291 [PubMed - indexed for MEDLINE]
Galactosemia
(as defined by the
National Organization for Rare Disorders)
also known as:
Galactose-1-Phosphate Uridyl Transferase Deficiency
GALT Deficiency
Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the bodyÕs ability to convert galactose (a sugar contained in milk, including human motherÕs milk) to glucose (a different type of sugar).
Galactose is converted to glucose by a series of three enzyme reactions.
The disorder is caused by a deficiency of an enzyme known as "galactose-1-phosphate uridyl transferase" which is vital to this process. Two variants of the gene for Galactosemia have been identified.
One causes a milder form of the disorder, while the other is the cause of a more severe form.
These variants can be distinguished by differences in galactose metabolism since each affects a different step in the conversion process. Because milk is the staple of an infant's diet, early diagnosis and treatment of this disorder is absolutely essential to avoid serious lifelong disability.
updated 8/04
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