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Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

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the gene. In 80% of people who have clear symptoms of PMD, a mutation can be found in the PLP gene. If a mutation in the PLP gene has been identified in a family member, testing on another child suspected of having PMD is possible to look at the mutation known to cause PMD in the family.

Treatment and management

There is no treatment or cure for PMD. Medical management is aimed at making life as full as possible and keeping people free from illness. Different types of therapy might be suggested. An occupational therapist can suggest adaptive devices to make it easier for an affected person to get around his or her home and perform everyday activities such as eating and using the bathroom. For example they may suggest installing bars to use in the bathroom or shower or special utensils for eating. Physical therapy can be helpful for reducing spasticity. Some patients with PMD require a feeding tube to help take in more calories. There are also medications that can assist in treating spasticity and seizures.

Prenatal testing

Testing during pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a specific PLP mutation. This can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS), which involves removing a tiny piece of the placenta and examining the cells. It can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with them. Couples interested in these options should have genetic counseling to carefully explore all of the benefits and limitations of these procedures.

Another procedure, called preimplantation diagnosis, allows a couple to have a child that is unaffected with the genetic condition in their family. This procedure is experimental and not available for all conditions. Those interested in learning more about this procedure should check with their doctor or genetic counselor.

Prognosis

The prognosis for patients with PMD varies in part due to the severity of the symptoms. The quality of care that patients receive also makes a difference in their quality of life. Boys with connatal PMD may die in infancy or early childhood, although some have survived into their 30s. Those with classic PMD or with the

K E Y T E R M S

Central nervous system (CNS)—In humans, the central nervous system is composed of the brain, the cranial nerves and the spinal cord. It is responsible for the coordination and control of all body activities.

Leukodystrophy—A disease that affects the white matter called myelin in the CNS.

Myelin—An insulation that is wrapped around the nerves in the body. In the central nervous system it is also called the white matter.

Nystagmus—Involuntary, rhythmic movement of the eye.

Proteolipid protein gene (PLP)—A gene that makes a protein that is part of the myelin in the central nervous system. Mutations in this gene cause PMD.

Spasticity—Increased muscle tone, or stiffness, which leads to uncontrolled, awkward movements.

PLP null syndrome usually reach adulthood, and some have survived into their 70s. The symptoms of PMD usually progress very slowly and some people have a plateau of their symptoms over time. Some people may seem to get worse over time but it is likely to be due to factors such as growth spurts, poor nutrition, or frequent illness and not because of progression of the disease. Most patients with PMD die from pulmonary or breathing difficulties.

Resources

PERIODICALS

Cailloux, F., F. Gauthier-Barichard, C. Mimault, V. Isabelle, V. Courtois, G. Giraud, B. Dastugue, O. Boespflug-Tanguy, and the Clinical European Network on Brain Dysmyelinating Disease. “Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations.” European Journal of Human Genetics 8, no. 5 (November 2000): 837–45.

Garbern, J., F. Cambi, M. Shy, and J. Kamholz. “The molecular pathogenesis of Pelizaeus-Merzbacher disease.” Archives of Neurology 56 (October 1999): 1210–14.

Yool, D.A., J.M. Edgar, P. Montague, and S. Malcolm. “The proteolipid protein gene and myelin disorders in man and animal models.” Human Molecular Genetics 9, no. 6 (2000): 987–992.

disease Merzbacher-Pelizaeus

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ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

PMD Foundation. Contact: Mike Laprocido, (609) 636-2482. United Leukodystrophy Foundation. 2304 Highland Dr.,

Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. http://www. ulf.org .

WEBSITES

“Clinical Programs.” PMD Website at Wayne State University.

http://www.med.wayne.edu/neurology .

GeneClinics. http://www.geneclinics.org .

Online Mendelian Inheritance in Men. http://www.ncbi

.nlm.nih.gov/Omim .

Karen M. Krajewski, MS, CGC

I Pendred syndrome

Definition

Pendred syndrome is an inherited condition that causes hearing loss typically beginning at birth and usually leads to the development of an enlarged thyroid, called a goiter. The thyroid is a gland responsible for normal body growth and metabolism. People with Pendred syndrome often have altered development of certain bones in the inner ear and/or balance problems as well. Vaughan Pendred first described the presence of hearing loss and goiter in two sisters in 1896, and thus the condition became known as Pendred syndrome. Genetic research has identified a gene on chromosome number seven that is usually altered in people with Pendred syndrome.

Description

Pendred syndrome is sometimes called goiter-sen- sorineural deafness, due to the common existence of both goiter and a form of hearing loss called sensorineural hearing loss in affected individuals. In order to understand how goiter occurs, it is helpful to first understand how the thyroid gland normally works. The thyroid is located underneath the larynx (voice box), in the front of the neck. The main role of the thyroid is to trap iodine, an essential nutrient found in various foods as well as salt, and to use it to make two important hormones: T3 and T4. These thyroid hormones allow the body to grow normally and to increase the speed of metabolism (breakdown) of nutrients. The thyroid is able to create these hormones because of a series of chemical reactions. A portion of the brain called the hypothalamus is responsi-

ble for controlling many body functions. One of its functions is to make a chemical called thyroid releasing hormone (TRH). This hormone travels to another gland, called the anterior pituitary gland, which is located underneath the brain. The TRH stimulates the anterior pituitary gland, which makes a chemical called thyroid stimulating hormone (TSH). This hormone travels to the thyroid, and activates the release of T3 and T4 into the body.

The word goiter is used to describe an enlargement of the thyroid gland. People with goiter may have hypothyroidism (they make too little T3/T4), hyperthyroidism (they make too much T3/T4), or they may have thyroid glands that work normally. Approximately 44–50% of people with Pendred syndrome have hypothyroidism, while the remaining 50–56% have thyroid glands that create a normal amount of thyroid hormones. However, approximately 75% develop goiter at some point in time, although it is rarely present at birth. Thirty to 40% of individuals develop an enlarged thyroid in late childhood or during their early teen-age years. The remaining 60–70% show symptoms during their early adult years. The enlargement of the thyroid gland happens because the mechanisms that control iodine transfer within the cells of the thyroid do not work well. This transfer is necessary to allow the iodine to bind to (and in doing so, help generate) thyroid hormones stored inside the thyroid. Since the iodine is not moved to the correct area of the thyroid, it becomes “pooled,” rather than attaching itself to thyroid hormones. This faulty processing of iodine among people with Pendred syndrome can often be confirmed by the use of a perchlorate discharge test. Perchlorate is a chemical that causes the pooled iodine to be pushed out of the thyroid into the bloodstream where it can be measured. Since people with Pendred syndrome usually have more pooled iodine than normal, they will push out or discharge a larger amount of iodine when they are exposed to perchlorate. However, not all affected individuals show abnormal results, so the test is not perfect.

Pendred syndrome causes a specific type of hearing impairment called sensorineural hearing loss (SNHL). The ear can be divided into three main parts: the outer ear, the middle ear, and the inner ear. The parts of the outer ear include the pinna (the visible portion of the ear), the ear canal, and the eardrum. The pinna directs sound waves from the environment through the ear canal, toward the eardrum. The eardrum vibrates, and causes tiny bones (called ossicles), which are located in the middle ear, to move. This movement causes pressure changes in fluids surrounding the parts that make up the inner ear. The main structures of the inner ear are the cochlea and the vestibular system. These structures send information

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K E Y T E R M S

Cochlea—A bony structure shaped like a snail shell located in the inner ear. It is responsible for changing sound waves from the environment into electrical messages that the brain can understand, so people can hear.

Cochlear implantation—A surgical procedure in which a small electronic device is placed under the skin behind the ear and is attached to a wire that stimulates the inner ear, allowing people who have hearing loss to hear useful sounds.

Enlarged vestibular aqueduct (EVA)—An enlargement of a structure inside the inner ear called the vestibular aqueduct, which is a narrow canal that allows fluid to move within the inner ear. EVA is seen in approximately 10% of people who have sensorineural hearing loss.

Goiter—An enlargement of the thyroid gland, causing tissue swelling that may be seen and/or felt in the front of the neck. May occur in people who have overactive production of thyroid hormones (hyperthyroidism), decreased production of thyroid hormones (hypothyroidism), or among people who have normal production of thyroid hormones.

Metabolism—The total combination of all of the chemical processes that occur within cells and tissues of a living body.

Pendrin—A protein encoded by the PDS (Pendred syndrome) gene located on chromosome 7q31.

Pendrin protein is believed to transport iodide and chloride within the thyroid and the inner ear.

Perchlorate discharge test—A test used to check for Pendred syndrome by measuring the amount of iodine stored inside the thyroid gland. Individuals with Pendred syndrome usually have more iodine stored than normal, and thus their thyroid will release a large amount of iodine into the bloodstream when they are exposed to a chemical called perchlorate.

Sensorineural hearing loss (SNHL)—Sensorineural hearing loss occurs when parts of the inner ear, such as the cochlea and/or auditory nerve, do not work correctly. It is often defined as mild, moderate, severe, or profound, depending upon how much sound can be heard by the affected individual. SNHL can occur by itself, or as part of a genetic condition such as Pendred syndrome.

Thyroid gland—A gland located in the front of the neck that is responsible for normal body growth and metabolism. The thyroid traps a nutrient called iodine and uses it to make thyroid hormones, which allow for the breakdown of nutrients needed for growth, development and body maintenance.

Vestibular system—A complex organ located inside the inner ear that sends messages to the brain about movement and body position. Allows people to maintain their balance when moving by sensing changes in their direction and speed.

regarding hearing and balance to the brain. The cochlea is shaped like a snail shell, and it contains specialized sensory cells (called hair cells) that change the sound waves into electrical messages. These messages are then sent to the brain through a nerve (called the auditory nerve) that allows the brain to “hear” sounds from the environment. The vestibular system is a specialized organ that helps people maintain their balance. The vestibular system contains three structures called semi-circular canals, which send electrical messages to the brain about movement and body position. This allows people to maintain their balance when moving by sensing changes in their direction and speed.

Sensorineural hearing loss occurs when parts of the inner ear (including the cochlea and/or auditory nerve) do not work correctly. The amount (or degree) of hearing loss can be described by measuring the hearing threshold (the sound level that a person can just barely hear) in

decibels (dB). The greater a person’s dB hearing level, the louder the sound must be to just barely be heard. Hearing loss is often defined as mild, moderate, severe, or profound. For people with mild hearing loss (26–45 dB), understanding conversations in a noisy environment, at a distance, or with a soft-spoken person is difficult. Moderate hearing loss (46–65 dB) causes people to have difficulty understanding conversations, even if the environment is quiet. People with severe hearing loss (66–85 dB) have difficulty hearing conversation unless the speaker is standing nearby or is talking loudly. Profound hearing loss (greater than 85 dB) may prevent people from hearing sounds from their environment or even loud conversation. People with Pendred syndrome generally have severe to profound SNHL that is congenital (i.e. present at birth) in both ears. However, some affected individuals develop SNHL during childhood, after they have learned to speak.

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People with SNHL often undergo specialized imaging tests, such as computed tomography (CT) and/or magnetic resonance imaging (MRI) scans, which create detailed images of the tissue and bone structures of the inner ear. Approximately 85% of people affected with Pendred syndrome have physical changes in the inner ear that can be seen with these tests. A common finding is a visible change in the snail-shaped cochlea called a Mondini malformation, in which the cochlea is underdeveloped and has too few coils compared to a normal cochlea. Another visible change sometimes seen in the inner ear is called enlarged vestibular aqueduct. The vestibular aqueduct is a narrow canal that allows fluid to move within the inner ear. Enlarged vestibular aqueduct (EVA) is the most common form of inner ear abnormality that is seen with CT or MRI scans. As the name implies, the vestibular aqueduct (canal) is larger than normal in people with EVA. Although EVA is seen in approximately 10–12% of people who are born with SNHL, some people with EVA can have SNHL that fluctuates (comes and goes) or is progressive (gradually worsening) as well as balance problems. In spite of the fact that Pendred syndrome has typically been diagnosed among people with both SNHL and goiter/thyroid problems, as of 2000, preliminary studies support the finding that some people with EVA and SNHL have a form of Pendred syndrome, even if they do not have goiter or thyroid problems.

Pendred syndrome also causes vestibular dysfunction in approximately 66% of affected individuals, which means they have abnormalities in their vestibular (balance) system. This may cause problems such as dizziness because they cannot sense changes in direction or speed when they are moving.

Genetic profile

Pendred syndrome is inherited in an autosomal recessive manner. “Autosomal” means that males and females are equally likely to be affected. “Recessive” refers to a specific type of inheritance in which both copies of a person’s gene pair (i.e. both alleles) need to be changed or altered in order for the condition to develop. In this situation, an affected individual receives an altered copy of the same gene from each parent. If the parents are not affected, they each have one working copy of the gene and one non-working (altered) copy, and are only “carriers” for Pendred syndrome. The chance that two carrier parents will have a child affected with Pendred syndrome is 25% for each pregnancy. They also have a 50% chance to have an unaffected child who is simply a carrier, and a 25% chance to have an unaffected child who is not a carrier, with each pregnancy.

The gene for Pendred syndrome is located on chromosome 7q31 and has been named the PDS gene. The gene tells the body how to make a specific protein called pendrin. The pendrin protein is believed to be responsible for transporting negatively charged elements called iodide and chloride (forms of iodine and chlorine) within the thyroid and likely the inner ear as well. Changes within the PDS gene create an altered form of pendrin protein that does not work properly, and thus causes the symptoms of Pendred syndrome. As of March 2001, genetic researchers identified at least 47 different types of alterations in the PDS gene among different families. However, four of these are more common than the others, and it is estimated that approximately 75% of affected people have these common changes.

Genetic research on the PDS gene has revealed that different types of gene changes can lead to different symptoms. For example, changes that completely inactivate the pendrin protein have been seen among people with Pendred syndrome (i.e. SNHL and goiter), whereas other types of alterations that only decrease the activity of pendrin have been found in people who have an inherited form of deafness called DFNB4. These individuals do have SNHL, but do not develop goiter. The researchers who published this finding in 2000 believed that the small amount of pendrin activity in these individuals likely prevented or delayed the symptoms of goiter. Another study published in 2000 showed that a large portion (greater than 80%) of people with EVA and SNHL were found to have one or more changes in the PDS gene, even though they did not all have thyroid changes such as goiter or abnormal perchlorate discharge test results. Thus, it is believed that changes in the pendrin gene actually cause a number of overlapping conditions. These conditions range from Pendred syndrome (i.e. SNHL and thyroid changes) to SNHL with EVA.

Demographics

Pendred syndrome has been estimated to occur in approximately 7.5 in 100,000 births in Great Britain, and one in 100,000 births in Scandinavia. It has been diagnosed in many different ethnic groups, including Japanese, East Indian, and other Caucasian groups, as well as among people of African descent. Inherited forms of congenital SNHL occur in approximately one of every 2,000 children. Prior to the discovery of the PDS gene, researchers estimated that up to 10% of all children born with SNHL could actually have Pendred syndrome. However, the percentage may be even higher. This is because changes in the PDS gene have been found in people who have SNHL and EVA, even though they do not have thyroid changes that would have helped make a clear diagnosis of Pendred syndrome in the past. Thus,

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future genetic studies on large groups of individuals with SNHL will help researchers understand how common Pendred syndrome truly is, as well as the range of symptoms that are caused by changes in the PDS gene.

Signs and symptoms

Although the symptoms of Pendred syndrome can vary among different individuals, the findings may include:

Sensorineural hearing loss that is usually congenital

Thyroid changes such as goiter, abnormal perchlorate discharge test results, and/or hypothyroidism

Inner ear changes, such as enlarged vestibular aqueduct (EVA) or Mondini malformation

Altered vestibular function that leads to balance problems

Diagnosis

The diagnosis of Pendred syndrome is typically based upon the results from a variety of tests that measure hearing, thyroid appearance/function, inner ear structure, and balance. Sometimes the diagnosis is not made until a person with SNHL reaches adolescence or adulthood and develops thyroid problems such as goiter or hypothyroidism. These problems are usually detected by physical examination and blood tests, and thus help diagnose Pendred syndrome. However, children who are born with SNHL often undergo special imaging tests such as CT or MRI scans. These may show inner ear changes that raise the question of possible changes in the PDS gene, even if the children do not have thyroid problems. In each of these situations, genetic testing may provide useful information that can confirm the diagnosis of Pendred syndrome.

Genetic research testing can be done for people with suspected or known Pendred syndrome by studying their DNA. The laboratory can check for the four common changes and some unique changes that have been found in the PDS gene. If this testing identifies an affected person’s specific genetic changes, other people in the same family who are not affected can have their DNA examined as well. This can determine whether an unaffected person is a carrier for Pendred syndrome or not. In addition, testing could be done during a pregnancy if both of a baby’s parents are carriers and have each had specific changes diagnosed in their DNA.

If genetic testing is done for people with known or suspected Pendred syndrome and the laboratory finds only one changed gene or no changes in the PDS gene, the diagnosis of Pendred syndrome cannot be confirmed. However, this does not rule out the possibility of Pendred

syndrome. Sometimes this happens simply because the affected person has a very unique change in the PDS gene that the lab cannot clearly identify. Over time, further genetic research could potentially provide useful information about their specific genetic changes as knowledge about the PDS gene grows.

Treatment and management

As of 2001, there is no cure for Pendred syndrome. However, there are several ways to treat some of the symptoms.

Treatment and management of SNHL

Regular visits with an audiologist (a hearing specialist) and an ENT (a physician specializing in the ear, nose, and throat) are important for people with Pendred syndrome. Hearing tests are necessary to check for changes in hearing ability, especially if people have milder forms of hearing loss and have some ability to hear. Among people with milder forms of hearing loss, hearing aids and speech therapy may be useful. However, people with profound SNHL and their families usually benefit from sign language training, which provides a good method of communication. Some people with severe to profound forms of hearing loss may also consider a procedure called cochlear implantation, in which a small electronic device is surgically placed behind the ear (underneath the skin) and is attached to a wire that stimulates the inner ear. This may allow people to hear useful sounds.

Treatment and management of thyroid problems

Regular examinations by an endocrinologist (a physician specializing in the treatment of hormone problems) who is familiar with Pendred syndrome is important. People who develop goiter and/or hypothyroidism are sometimes treated with a medication called thyroxine, which is basically the hormone called T4. Other people with goiter have most of their thyroid surgically removed. However, this form of treatment is not a cure, and the remaining thyroid tissue can grow and redevelop into goiter again. Among some people, the goiter does not require treatment or it simply disappears on its own.

There are a number of support groups available that provide education, support and advice to help people cope with the symptoms of SNHL and thyroid problems that often occur among individuals with Pendred syndrome.

Prognosis

Pendred syndrome does not cause a shortened life span for affected individuals. Those who develop hypothyroidism and do not seek treatment may experience

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a variety of health problems including low energy level, weight gain, constipation, and dry skin. However, hypothyroidism and goiter can usually be well managed with medication or surgery. The degree of hearing loss that occurs is typically severe to profound from an early age and usually changes very little over the years. However, among affected people who develop SNHL during childhood (after learning to speak), the degree of hearing loss can worsen over time. Sign language training (and sometimes cochlear implants) allow alternative methods of communication and thus help people reach their full potential. Support groups for people with hearing loss often help individuals with SNHL (whether due to Pendred syndrome or other causes) maintain and/or improve their quality of life as well.

Resources

BOOKS

Gorlin, R. J., H. V. Toriello, and M. M. Cohen. “Goiter and profound congenital sensorineural hearing loss (Pendred syndrome).” In Hereditary Hearing Loss and Its Syndromes.

Oxford Monographs on Medical Genetics No. 28. New York and Oxford: Oxford University Press, 1995.

PERIODICALS

Reardon, William, et al. “Prevalence, age of onset, and natural history of thyroid disease in Pendred syndrome.” Journal of Medical Genetics 36 (August 1999): 595–98.

Reardon, William, et al. “Enlarged vestibular aqueduct: a radiological marker of Pendred syndrome, and mutation of the PDS gene.” Quarterly Journal of Medicine 93, no. 2 (2000): 99–104.

Scott, Daryl A., et al. “Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4).” Human Molecular Genetics 9, no. 11 (2000): 1709–15.

Scott, Daryl A., et al. “The Pendred syndrome gene encodes a chloride-iodide transport protein.” Nature Genetics 21, no. 4 (April 1999): 440–43.

ORGANIZATIONS

American Society for Deaf Children. PO Box 3355, Gettysburg, PA 17325. (800) 942-ASDC or (717) 3347922 v/tty. http://www.deafchildren.org/asdc2k/home/ home.shtml .

American Thyroid Association. Townhouse Office Park, 55 Old Nyack Turnpike, Ste. 611, Nanuet, NY 10954.http://www.thyroid.org .

Boys Town National Research Hospital. 555 N. 30th St., Omaha, NE 68131. (402) 498-6749. http://www

.boystown.org/Btnrh/Index.htm .

National Association of the Deaf. 814 Thayer, Suite 250, Silver Spring, MD 20910-4500. (301) 587-1788. nadinfo @nad.org. http://www.nad.org .

National Institute on Deafness and Other Communication Disorders. 31 Center Dr., MSC 2320, Bethesda, MD 20814. http://www.nidcd.nih.gov .

Vestibular Disorders Association. PO Box 4467, Portland, OR 97208-4467. (800) 837-8428. http://www.vestibular

.org .

WEBSITES

Smith, Richard R. J., MD, and Guy Van Camp, PhD. “Pendred Syndrome.” GeneClinics. University of Washington, Seattle. http://www.geneclinics.org/profiles/pendred17 . (May 2001).

Pamela J. Nutting, MS, CGC

Pepper syndrome see Cohen syndrome

Perinatal sudanophilic leukodystropy see

Pelizaeus-Merzbacher disease

Peroutka sneeze see Achoo syndrome

I Pervasive developmental disorders

Definition

The pervasive developmental disorders, or PDDs, are a group of childhood disorders that manifest during the first years of the child’s life. They are marked by severe weaknesses in several areas of development: social interaction, communication, or the appearance of stereotyped behavior patterns and interests. The PDDs are also known as autistic spectrum disorders. As the phrase spectrum disorder suggests, persons with these disorders fall at different points along a fairly wide continuum of disabilities and associated disorders. As defined by DSM-IV, the pervasive developmental disorders include:

autistic disorder

Rett syndrome

childhood disintegrative disorder (CDD)

Asperger syndrome

pervasive developmental disorder not otherwise specified (PDD-NOS)

Description

The PDDs form a diagnostic category intended to identify children with delays in or deviant forms of social, linguistic, cognitive, and motor (muscular movement) development. The category covers children with a wide variety of developmental delays of differing severity in these four broad areas. The precise cause(s) of the

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PDDs are still obscure, but are assumed to be abnormalities of the central nervous system.

Autistic disorder

Autistic disorder, or autism, was first described in 1943. Autistic children are characterized by severe impairment in their interactions with others and delayed or abnormal patterns of communication; about 50% of autistic children do not speak at all. These abnormalities begin in the first weeks of life; it is not unusual for the parents of an autistic child to say that they “knew something was wrong” quite early in the child’s development. Another characteristic symptom has been termed “insistence on sameness;” that is, these children may become extremely upset by trivial changes in their environment or daily rou- tine—such as a new picture on the wall or taking a different route to the grocery store. Autistic children often make repetitive or stereotyped gestures or movements with their hands or bodies. Their behavioral symptoms may also include impulsivity, aggressiveness, temper tantrums, and self-biting or other forms of self-injury.

About 75% of children diagnosed with autism are also diagnosed with moderate mental retardation (IQ between 35 and 50). Their cognitive skills frequently develop unevenly, regardless of their general intelligence level. A minority of autistic children have IQs above 70; their condition is sometimes called high-functioning autism, or HFA. In addition to mental retardation, autism is frequently associated with other neurological or medical conditions, including encephalitis, phenylketonuria, tuberous sclerosis, fragile X syndrome, and underdeveloped reflexes. About 25% of autistic children develop seizure disorders, most often in adolescence.

Rett syndrome

Unlike autism, Rett syndrome has a very distinctive onset and course. The child develops normally during the first five months of life; after the fifth month, head growth slows down and the child loses whatever purposeful hand movements she had developed during the first five months. After 30 months, the child frequently develops repetitive hand-washing or hand-wringing gestures; over 50% of children with the disorder will develop seizure disorders. Rett syndrome is also associated with severe or profound mental retardation. As of 2001, this disorder has been diagnosed only in females.

Childhood disintegrative disorder (Heller’s syndrome)

Childhood disintegrative disorder, or CDD, was first described by an educator named Theodore Heller in 1908. He referred to it as dementia infantilis. Children

with CDD have apparently normal development during the first two years of life. Between two and ten years of age, the child loses two or more previously acquired skills, including language skills, social skills, toileting, self-help skills, or motor skills. The child may also lose interest in his or her surroundings, and often comes to “look autistic.” The data available as of 2001 indicate that CDD has several different patterns of onset and development; it may develop rapidly (within weeks) or more slowly (over a period of months).

CDD is frequently associated with severe mental retardation. In addition, children with CDD have a higher risk of seizures. CDD is occasionally associated with general medical conditions (metachromatic leukodystrophy or Schilder’s disease) that could account for the developmental losses, but in most cases there is no known medical cause of the child’s symptoms.

Asperger syndrome

Asperger syndrome (AS) was first identified in 1944 by a Viennese psychiatrist. It is sometimes called autistic psychopathy. AS is distinguished from autism by later onset of symptoms; these children usually develop normally for the first few years of life and retain relatively strong verbal and self-help skills. They are often physically clumsy or awkward, however, and this symptom may be noticed before the child starts school. AS is diagnosed most frequently when the child is between five and nine years of age. One of the distinctive features of Asperger syndrome is an abnormal degree of fascination or preoccupation with a limited or restricted subject of interest, such as railroad timetables, the weather, astronomical data, French verb forms, etc. In addition, the child’s knowledge of the topic reflects rote memorization of facts rather than deep understanding.

Unlike autism, AS does not appear to be associated with a higher risk of seizure disorders or such general conditions as fragile X syndrome.

Pervasive developmental disorder not otherwise specified

PDD-NOS is regarded as a “sub-threshold” category, which means that it covers cases in which the child has some impairment of social interaction and communication, or has some stereotyped patterns of behavior, but does not meet the full criteria for another PDD. PDDNOS is sometimes referred to as atypical personality development, atypical autism, or atypical PDD. No diagnostic criteria specific to this category are provided in DSM-IV. Little research has been done on children diagnosed with PDD-NOS because the condition has no clear definition. The available data indicate that children

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K E Y T E R M S

Atypical personality development—Another term for pervasive development disorder (PDD-NOS). Other synonyms for this diagnostic category are atypical autism and atypical PDD.

Autistic psychopathy—Hans Asperger’s original name for Asperger syndrome. It is still used occasionally as a synonym for the disorder.

Autistic spectrum disorders—Another term for the pervasive developmental disorders.

Heller’s syndrome—Another name for Childhood Disintegrative Disorder (CDD). It is also sometimes called dementia infantilis.

Kanner’s syndrome—Another name for autism.

placed in this category are diagnosed at later ages than children with autism, and are less likely to have mental impairment.

Genetic profile

Of the PDDs, autism has the best-documented genetic component, although more research is required. It is known that the degree of similarity in a pair of twins with respect to autism is significantly higher in identical than in fraternal twins. The likelihood of the biological parents of an autistic child having another child with the disorder is thought to be about 1:20. It is possible that the actual rate is higher, since many parents of one autistic child decide against having more children.

The genetic profile of Asperger syndrome is less well known, although the disorder appears to run in fam- ilies—most commonly families with histories of depression or bipolar disorder. Rett syndrome is known only from case studies, so data about its genetic profile is not available as of 2001. The same lack of information is true also of CDD—partly because the disorder was first reported in 1966 and has only been officially recognized since 1994, and partly because the condition has been frequently misdiagnosed.

Demographics

Autism is thought to affect between two and five children out of every 10,000. Childhood disintegrative disorder is much less frequent, perhaps only a tenth as common as autism. Rett syndrome is also very rare, and is known only from case series reported in the medical literature. The incidence of Asperger syndrome is not

definitely known as of 2001, but is thought to lie somewhere between 0.024% and 0.36% of the general population.

Some of the PDDs are considerably more common in boys than in girls. The male to female sex ratio in autism is variously given as 4:1 or 5:1. Less is known about the incidence of Asperger syndrome, but one study reported a male/female ratio of 4:1. Initial studies of CDD suggested an equal sex ratio, but more recent data indicate that the disorder is more common among males. Rett syndrome, on the other hand, has been reported only in females.

Signs and symptoms

The signs and symptoms of each PDD are included in its description.

Diagnosis

The differential diagnosis of autistic spectrum disorders is complicated by several factors. One is the wide variation in normal rates of children’s development. In addition, because some of the symptoms of autism are present in mental retardation, it can be difficult to determine which condition is present in a specific child, or whether both conditions are present. A definitive diagnosis of autism is rarely given to children below the age of three years. Delays or abnormal patterns in cognitive and social development can be more accurately assessed in children age three or four; children with AS or PDDNOS may not be diagnosed until age five or later. A third factor is the tangled history of differential diagnosis of childhood disorders. Autism was first described by a physician named Leo Kanner in 1943. For several decades after Kanner’s initial observations, researchers assumed that there was an association or continuity between autism in children and schizophrenia in adults. In fact, the term autism was first used to describe the self-focused thinking that characterizes schizophrenia; it was only later that the word was applied to the severe impairment of social behaviors that is a major symptom of autistic disorder. It took years of further research to establish clear diagnostic distinctions between autism and schizophrenia. Furthermore, the early assumption of a connection between autism and schizophrenia led to the hypothesis that autism was caused by painful experiences in early childhood. It is now known that autism and the other PDDs are essentially neurological disturbances.

Medical or laboratory testing

As of 2001, there are no brain imaging studies or laboratory tests that can be performed to diagnose a per-

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vasive developmental disorder. The examiner may, however, recommend a hearing test to rule out deafness as a possible cause of a child’s failure to respond to the environment, or a brain scan to rule out other physical conditions.

Diagnostic interviews

A PDD may be diagnosed by a pediatrician, pediatric neurologist, psychologist, or specialist in child psychiatry. The diagnosis is usually based on a combination of the child’s medical and developmental history and clinical interviews or observations of the child. Children who cannot talk can be evaluated for their patterns of nonverbal communication with familiar as well as unfamiliar people. The parents may be asked to describe the child’s use of eye contact, gestures, facial expressions, and body language. A clinical psychologist can administer special tests designed to evaluate the child’s problemsolving abilities without the use of language.

Diagnostic questionnaires and other tools

The examiner may use a diagnostic checklist or screener such as the Childhood Autism Rating Scale, or CARS, which was developed in 1993. In addition, the Autism Research Institute (ARI) distributes a Form E-2 questionnaire that can be completed by the parents of a child with a PDD and returned to ARI. Form E-2 is not a diagnostic instrument as such but a checklist that assists ARI in the compilation of a database of symptoms and behaviors associated with autistic spectrum disorders. Parents who complete the form will receive a brief report about their child. Researchers expect that the database will help to improve the accuracy of differential diagnosis as well as contribute to more effective treatments for children with PDDs.

Treatment and management

The treatment and management of children with PDDs will vary considerably according to the severity of the child’s impairment and the specific areas of impairment.

Medications

As of 2001, there are no medications that can cure any of the PDDs, and no single medication that is recommended for the symptoms of all children with PDDs. In addition, there are few comparative medication studies of children with autistic spectrum disorders. The five sites (UCLA, University of Indiana, Ohio State, Yale, and the Kennedy-Krieger Institute) involved in the Research Units in Pediatric Psychopharmacology (RUPP) Program

are currently conducting a study of respiridone in PDD children with behavioral problems. The RUPP sites are also testing medications approved for use in adults with self-injuring behaviors, anxiety, aggressive behavior, and obsessive-compulsive disorder on children with PDDs. This research is expected to improve the available treatments for children with these disorders.

Psychotherapy

The only PDD patients who benefit from individual psychotherapy are persons with AS or with HFA who are intelligent enough to have some insight into their condition. Typically they become depressed in adolescence or adult life when they recognize the nature and extent of their social disabiliities.

Educational considerations

Most children with AS and some children with highfunctioning autism are educable. Many people with AS, in fact, successfully complete graduate or professional school. Only a small percentage of autistic children, however, complete enough schooling to be able to live independently as adults. Children with CDD must be placed in schools for the severely disabled.

Employment

Most children with AS can finish school and enter the job market. They do best, however, in occupations that have regular routines or allow them to work in isolation. Only a few high-functioning autistic children are potentially employable.

Prognosis

The PDDs as a group are lifelong disorders, but the prognoses vary according to the child’s degree of impairment. As a general rule, language skills and the child’s overall IQ are the most important factors in the prognosis. Children with AS have the most favorable educational prognosis but usually retain some degree of social impairment even as adults. Of autistic children, only about one-third achieve partial or complete independence in adult life. The prognoses for Rett syndrome and CDD are worse than that for autism, as the skill levels of these children often continue to deteriorate. Some, however, make very modest developmental gains in adolescence. Lastly, current information about the prognoses of children with PDDs is derived from treatments given to patients in the 1970s or 1980s. As knowledge of effective treatments for PDDs continues to accumulate, children with these disorders receive treatment earlier than they did two decades ago. It is likely that future prognoses for the PDDs will reflect these improvements.

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Peutz-Jeghers syndrome

Resources

BOOKS

American Psychiatric Association Staff. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, revised. Washington, DC: American Psychiatric Association, 2000.

“Psychiatric Conditions in Childhood and Adolescence.” In The Merck Manual of Diagnosis and Therapy. Edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 1999.

Thoene, Jess G., ed. Physicians’ Guide to Rare Diseases.

Montvale, NJ: Dowden Publishing Company, 1995. Waltz, Mitzi. Pervasive Developmental Disorders: Finding a

Diagnosis and Getting Help. New York: O’Reilly & Associates, Inc., 1999.

PERIODICALS

Autism Research Institute. Autism Research Review

International. San Diego, Calif.: 1987.

ORGANIZATIONS

Autism Research Institute. 4182 Adams Ave., San Diego, 92116. Fax: (619) 563-6840.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

Yale-LDA Social Learning Disabilities Project. Yale Child Study Center, 230 South Frontage Road, New Haven, CT 06520-7900. (203) 785-3488. http://info.med.Yale.edu/ chldstdy/autism .

WEBSITES

Center for the Study of Autism Home Page, maintained by Stephen Edelson, PhD. http://www.autism.org .

Yale Child Study Center.http://info.med.Yale.edu/chldstdy/autism .

Rebecca J. Frey, PhD

I Peutz-Jeghers syndrome

Definition

Peutz-Jeghers syndrome (PJS) is named after two doctors who first studied and described it in 1921. It is an association of three very specific conditions in any one person. The first condition is the appearance of freckles on parts of the body where freckles are not normally found. The second condition is the presence of multiple gastrointestinal polyps. The third condition is a risk, greater than the risk seen in the general population, of developing certain kinds of cancers.

Description

The freckles associated with PJS are dark brown, dark blue, or greenish black. In almost all people with PJS, these freckles are present at birth on the lining of the cheeks inside the mouth. By the time most children reach one or two years old, freckles develop around the lips, nostrils, eyes, anus, and genitals. This is in contrast to ordinary freckles, which are absent at birth and rarely develop in these locations. The freckles seen in PJS are sometimes called macules (discolored spot or patch on the skin of various colors, sizes, and shapes), or areas of hyperpigmentation (increased pigmentation of the skin).

Some people with PJS also have these freckles on the palms of their hands or feet or on their fingertips. Freckles may merge together. The freckles on the skin often fade or disappear by adolescence, but the freckles inside the mouth generally remain throughout the person’s life.

Gastrointestinal polyps can develop in children as young as one or two years old. The age at which polyps appear and the number of polyps vary widely from patient to patient. The polyps can occur in infants and cause spasms and pain in the abdomen. On average, polyps appear by the time a child with PJS is 10 years old. There may be anywhere from dozens to hundreds of polyps throughout the gastrointestinal tract. For this reason, PJS is sometimes called polyposis, which means “too many polyps.” Most PJS polyps occur in the small intestine, but they can also develop in the esophagus, stomach, and colon. In some people with PJS, polyps have been found in the mouth or nose.

The polyps seen in PJS have a unique structure. They consist of overgrowths of normal tissue that smooth muscle bands of the stomach and instestines run through. This kind of overgrowth is called a hamartoma. Consequently, PJS is sometimes called hamartomatous intestinal polyposis. A hamartoma is a non-cancerous tumor, and hamartomatous polyps are not cancerous. However, they can take up too much space, causing obstruction, pain, and even bleeding. They can also become cancerous, or malignant, if a genetic change results in uncontrolled cell growth.

It is this potential for malignant change that increases cancer risk in people with PJS. As might be expected, the gastrointestinal tract is the most common site for cancer in people with PJS. The small intestine, stomach, gallbladder, pancreas, colon, and rectum are all susceptible. However, cancer can also occur outside the gastrointestinal tract. When this happens, the sites most likely to be involved are the breasts, ovaries, uterus, cervix, or testicles.

PJS does not affect intelligence or behavior.

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