The Gale Genetic Disorders of encyclopedia vol 2 - part 8 docx

logical properties—that is, their physical composition and characteristic appearance under a microscope. As each hamartoma is comprised of different cellular ele- ments, each one has a particular name. For example, while both are hamartomas, a fibroma is comprised of connective tissue whereas a lipoma is made up of fat cells. While the organs affected vary from person to per- son, most people with TSC have some type of skin irreg- ularities called lesions. Some of the most commonly seen skin lesions are hypomelanotic macules—white or light patches sometimes in an ash-leaf shape and called Ash- leaf spots. Many people in the general population have one or two light areas of skin. However, the presence of three or more such macules in any one individual is con- sidered a major diagnostic finding of TSC. A second major diagnostic feature of the condition is the appear- ance of small, red bumps called fibromas, either on the face (facial angiofibromas) or around or under the finger- or toenails (ungual fibromas). In addition, rough patches of skin termed Shagreen patches are highly specific to a diagnosis of TSC. Finally, groups of small light circles called Confetti spots are considered a minor feature of the disorder. In contrast to skin lesions, brain lesions tend to be serious and are responsible for the neurological symp- toms and cognitive impairment seen in severely affected individuals. There are four primary abnormalities that can be detected by magnetic resonance imaging (MRI) or computer tomography (CT) scanning, the first of which are cortical tubers—nodular growths found in the cortex of the brain—and give tuberous sclerosis (literally “hard growths”) its name. Subependymal nodules are growths found underneath the lining of the ventricles in the brain and may cause no problems for the patient unless they grow or begin to block the flow of the cerebral spinal GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1151 Tuberous sclerosis complex KEY TERMS Bone cysts—Fluid- or air-filled space within the bones. Cardiac rhabdomyoma—Benign (non-cancerous) tumor of the heart muscle. Cerebral white matter migration lines—Pattern of defects found in the cerebral cortex of the brain probably caused by abnormal migration of neurons during brain formation. Confetti skin lesions—Numerous light or white spots seen on the skin that resemble confetti. Cortical tuber—Round (nodular) growth found in the cortex of the brain. Dental pits—Small, shallow holes or crevices in the tooth enamel. Facial angiofibromas—Benign (non-cancerous) tumors of the face. Forehead plaque—Flat, fibrous skin growth on the forehead. Gingival fibromas—Fibrous growths found on the gums. Hamartomatous rectal polyps—Benign (non-can- cerous) growths found in the rectum. Hypomelanotic macules—Patches of skin lighter than the surrounding skin. Lymphangiomyomatosis—Serious lung disease characterized by the overgrowth of an unusual type of muscle cell resulting in the blockage of air, blood, and lymph vessels to and from the lungs. Nonrenal hamartoma—Benign (non-cancerous) tumor-like growths not found in the kidneys that often disrupt the normal function of a particular organ system. Nontraumatic ungual or periungual fibroma— Fibrous growth that appears around the fingernails and/or toenails Renal angiomyolipoma—Benign (non-cancerous) tumors in the kidney that are made up of vascular tissue (angio), smooth muscle (myo), and fat (lipoma). Renal cysts—Fluid- or air-filled spaces within the kidneys. Retinal achromic patch—Defect in the coloration of the retina. Retinal hamartomas—Benign (non-cancerous) tumor found on the retina. Shagreen patch—Area of tough and dimpled skin. Subependymal giant cell astrocytoma—Benign (non-cancerous) tumor of the brain comprised of star-shaped cells (astrocytes). Subependymal nodule—Growth found underneath the lining of the ventricles in the brain. fluid. In contrast, subependymal giant cell astrocytomas, non-cancerous brain tumors comprised of star-shaped cells and found in about 5% of patients with TSC, can, if untreated, result in blindness, hydrocephalus (fluid on the brain), and even death. Finally, cerebral white matter migration lines may be seen through radiographic (x ray) studies and are considered a minor diagnostic feature of TSC. About 85% of affected individuals will develop epileptic seizures at some point in their lifetime, most beginning by the first year of life. Research suggests that early control of epilepsy by medication will decrease the chance of a child developing serious mental complica- tions. People with TSC have a range of mental abilities from normal to mild or moderate developmental delays and learning disabilities, to severe mental retardation. Autism, attention deficit hyperactivity disorder (ADHD), and other behavioral problems are seen in affected individuals. Fatty kidney tumors, known as renal angiomyolipo- mas, are one of the most common findings in TSC patients, affecting 70-80% of older children and adults, and often cause serious renal malfunction. In addition, the presence of multiple renal cysts (fluid filled areas within the kidneys) is suggestive of the condition. In addition to these benign growths, malignant kidney tumors may also develop. The most common cardiac symptom is one or more tumors (cardiac rhabdomyomas) in the heart. These tumors are almost exclusively seen in infants and young children and usually spontaneously disappear by late childhood, thereby avoiding the need for surgery. About 47-67% of infants and children with TSC have heart tumors and some females develop the rhabdomyomas when they reach puberty. Tuberous sclerosis complex affects the eyes in the form of retinal nodular hamartomas—multiple growths on the retina. A discoloration on the retina (retinal achromic patch) is also considered a minor feature of the condition. In addition to the above, symptoms of TSC may include dental pits in the teeth, growths in the rectum (hamartomatous rectal polyps), bone cysts, growths on the gums (gingival fibromas) and other non-specific growths (nonrenal hamartomas). Women with TSC may develop lymphangiomyomatosis, a serious lung disease. Furthermore, all individuals with TSC are at a higher risk over the general population for developing specific can- cers, with 2% of patients developing a malignant tumor in one of the affected body tissues such as kidney or brain. Diagnosis When a person exhibits signs of TSC or has a family history of the condition, an evaluation by a medical geneticist, neurologist, or other qualified professional is recommended to confirm (or rule out) the diagnosis and to recommend screening and management options for the individual. In addition, speaking with a genetic counselor may help families understand the genetics behind the dis- order, their recurrence risks (chances for having another affected family member) and the practical and psychoso- cial implications of the disease on their personal situation. Detection of hypomelanotic macules (light patches on the skin) can be performed quickly and easily using a special ultraviolet lamp called a Wood’s lamp. This light emphasizes the lightened areas on the skin that may oth- erwise be difficult to see using normal light. Other skin lesions called fibromas are easily visible and identifiable due to their characteristic smooth form, red color, and their even distribution on the face and/or their protrusions among the nails on the fingers and toes. Radiographic imaging using ultrasound, MRI, or CT technology can detect growths present in the brain, kidneys, heart, and eyes. As basic understanding of and testing methods for tuberous sclerosis complex have improved, criteria used for confirming a diagnosis of tuberous sclerosis complex have been revised. The National Institutes of Health 1152 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Tuberous sclerosis complex A common sign of tuberous sclerosis is skin lesions called hypomelanotic macules.These are white or light patches of skin sometimes in an ash-leaf shape and called Ash-leaf spots. (Custom Medical Stock Photo, Inc.) (NIH) held a consensus conference on TSC in 1998 and published the following diagnostic criteria in 2000: Major features: • Facial angiofibromas or forehead plaque • Nontraumatic ungual or periungual fibroma • Hypomelanotic macules (more than three) • Shagreen patch • Multiple retinal hamartomas • Cortical tuber • Subependymal nodule • Subependymal giant cell astrocytoma • Cardiac rhabdomyoma (one or more) • Lymphangiomyomatosis • Renal angiomyolipoma Minor features: • Multiple randomly distributed dental pits • Hamartomatous rectal polyps • Bone cysts • Cerebral white matter migration lines • Gingival fibromas • Nonrenal hamartoma • Retinal achromic patch • Confetti skin lesions • Multiple renal cysts A confirmed diagnosis of TSC requires that a patient display either two major features or one major and two minor features, a suspected diagnosis one major and one minor feature, and a possible diagnosis one major or two minor features in any one individual. Treatment and management Optimal treatment for TSC is dependent upon proper disease management. The following should be performed on all patients with TSC at the time of diagnosis to con- firm a diagnosis of the disease as well as obtain baseline medical data for future evaluations: • dermatologic (skin) examination • fundoscopic (eye) examination • renal (kidney) imaging study • cardiac electrocardiogram (ECG) and echocardiogram (ECHO) • brain magnetic resonance imaging (MRI) Since the characteristic feature of tuberous sclero- sis complex is the growth of benign tumors, treatments are often focused on appropriate surgical interventions to arrest tumor growth or remove tumors whose growth has resulted in or may lead to medical complications especially in the kidney or brain. Regular brain MRI studies should be performed in children and adults with previous findings as clinically indicated and every one to three years in children and, less frequently, in adults without symptoms. In addition, periodic brain elec- troencephalogram (EEG) studies are recommended for both children and adult patients when clinically indi- cated. Children without previous kidney findings should be offered renal imaging studies using ultrasound, MRI, or CT scanning every three years until they reach adoles- cence and then, every one to three years as adults. Likewise, asymptomatic adults should have imaging of their kidneys every one to three years. Both children and adults who have kidney symptoms should be monitored using imaging studies every six months to one year until the tumor growth stabilizes or decreases. Any child with cardiac rhabdomyomas should be monitored every six months to one year until the tumor stabilizes or regresses completely. Adults with previous findings of cardiac tumors should be monitored as clini- cally recommended by their treating physician. While monitoring is important, cardiac rhabdomyomas, as well as retinal lesions and gingival fibromas, usually do not require treatment. In contrast to these benign tumors, cancerous tumors that develop in patients with TSC should be treated by an oncologist as appropriate. Facial angiofibromas and peri- and subungual fibro- mas on the nails are common symptoms in TSC patients. While they are generally not medically significant, they can cause skin irritations or be a cosmetic concern to the individual. Special techniques involving dermabrasion or laser therapy can be performed by a dermatologist or plastic surgeon to remove such growths. Patients with seizure disorders are prescribed spe- cific medications to control seizures. As of 2001, a new anti-epileptic drug (vigabatrin) has been shown to be an effective medication in infants with seizures and has been shown to improve long-term outcomes in behavioral and intellectual areas. In addition to con- trolling seizures, early intervention programs that include special education, behavior modification, physical and occupational therapies, and speech ther- apy is often recommended for individuals with learn- ing disabilities, developmental delays, mental retardation, autism, and other mental and emotional disorders. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1153 Tuberous sclerosis complex Neurodevelopmental testing is appropriate at the time of diagnosis for all children and should be per- formed every three years until adolescence and for any adult diagnosed with TSC who displays signs of impair- ment. Subsequent evaluations should be done on both children and adults with previous findings of develop- mental delays or problems. While present in only 1% of patients with TSC, almost exclusively in females, lung complications can be serious and even fatal. Symptoms may include sponta- neous pneumothorax (air in the chest cavity), dyspnea (difficult breathing), cough, hemoptysis (spitting of blood), and pulmonary failure. Therefore, a computed tomography (CT) scan of the lungs is recommended for any TSC patient who has symptoms of lung disease or complications and for all female TSC patients at the age of 18. Clinical trials involving Tamoxifen and proges- terone treatments have shown positive results in some patients with lung disease. Prognosis The lifespan of individuals with TSC varies with the severity of the condition in any one person. Many affected people have normal life expectancies and a high quality of life, relatively free of symptoms or complica- tion of the disease. Conversely, severely affected or dis- abled individuals may experience a shortened lifespan and a high rate of illness and medical complications. Therefore, proper disease management, diagnostic moni- toring, and follow-up are critical to achieving and main- taining optimal health in patients with TSC. Resources BOOKS Gomez, Manuel R., ed. Tuberous Sclerosis. New York: Raven Press, 1988. Gomez, Manuel R., Julian R. Sampson, and Vicky H. Whittemore, eds. Tuberous Sclerosis Complex. Oxford: Oxford University Press, 1999. Johnson, William G., and Manuel R. Gomez, eds. Tuberous Sclerosis and Allied Disorders: Clinical, Cellular, and Molecular Studies. New York: The New York Academy of Sciences, 1991. PERIODICALS Arbuckle, H. Alan, and Joseph G. Morelli. “Pigmentary Disorders: Update on Neurofibromatosis-1 and Tuberous Sclerosis.” Current Opinion in Pediatrics 12 (2000): 354- 358. Hyman, Mark H., and Vicky H. Whittemore. “National Institutes of Health Consensus Conference: Tuberous Sclerosis Complex.” Archives of Neurology 57 (May 2000): 662-665. Jambaque, I., et al. “Mental and Behavioural Outcome of Infantile Epilepsy Treated by Vigabatrin in Tuberous Sclerosis Patients.” Epilepsy Research 38 (2000): 151-160. O’Callaghan, Finbar J., and John P. Osborne. “Advances in the Understanding of Tuberous Sclerosis.” Archives of Disease in Childhood 83 (August 2000): 140-142. Sparagana, Steven P., and E. Steve Roach. “Tuberous Sclerosis Complex.” Current Opinion in Neurology 13 (2000):115- 119. ORGANIZATIONS Tuberous Sclerosis Alliance. 801 Roeder Rd., Suite 750, Silver Spring, MD 20910. (800) 225-6872. Ͻhttp://www.tsal- liance.orgϾ. WEBSITES Australasian Tuberous Sclerosis Society. Ͻhttp://www.netspace.net.au/~atss/Ͼ. The Global Tuberous Sclerosis Information Link. Ͻhttp://members.aol.com/gtsil/ts/index.htmϾ. Tuberous Sclerosis Alliance. Ͻhttp://www.tsalliance.orgϾ. The Tuberous Sclerosis Association. Ͻhttp://www.tuberous-sclerosis.org/Ͼ. Pamela E. Cohen, MS, CGC Turcot syndrome see Familial adenomatous polyposis I Turner syndrome Definition Turner syndrome is a chromosomal disorder affect- ing females wherein one of the two X-chromosomes is defective or completely absent. Description Chromosomes are structures in the nucleus of every cell in the human body. Chromosomes contain the genetic information necessary to direct the growth and normal functioning of all cells and systems of the body. A normal individual has a total of 46 chromosomes in each cell, two of which are responsible for determining gender. Normally, females have two X chromosomes and males have one X and one Y chromosome. In Turner syndrome, an error occurring very early in development results in an abnormal number and arrange- ment of chromosomes. Most commonly, an individual with Turner syndrome will be born with 45 chromosomes in each cell rather than 46. The missing chromosome is an X chromosome. The affected person is always female. 1154 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Turner syndrome Genetic profile Turner syndrome is a disorder associated with char- acteristic defects in the X chromosome. The most com- mon presentation is a female with a single X chromosome and an absent X chromosome. A Greek study from 1999 reported that the intact X chromosome was as likely to come from the mother as from the father. This means that there is no parental pattern of responsi- bility for the missing or defective X chromosome. Another less common genetic pattern for Turner syn- drome (35%) is a mosaic. A Danish study reported that mosaicism has an effect on malformations that are asso- ciated with Turner syndrome. Research reported in 1997 noted that the karyotype can have a significant effect on the growth of children with Turner syndrome. The exact location of the genes on the X chromo- some involved in Turner syndrome has not been deter- mined as of 2001. At present, evidence exists that there is a locus for stature on the distal portion of the short arm; there are loci for normal ovarian function on both the short and long arms; and there are loci contributing to fetal viability on the long arm of X. Demographics The prevalence of Turner syndrome is widely reported as being approximately one per 2,000 live female births although researchers have reported preva- lence rates that range from one in 3,125 to one in 5,000 live female births. About 1-2% of all female conceptions have a miss- ing X chromosome. Of these, the majority (99%) sponta- neously abort, usually during the first trimester of pregnancy. With ultrasound being used more frequently, researchers have realized that some pregnancies with a missing X chromosome that progress into the second trimester are associated with nuchal cysts, severe lym- phedema, or hydrops fetalis. These pregnancies are associated with a high frequency of fetal death. Signs and symptoms Turner syndrome is characterized by delayed growth that leads to a small stature and frequent infertility. Individuals with Turner syndrome report an increased incidence of fractures in childhood and osteoporotic frac- tures in adulthood. The incidence of diabetes mellitus (both insulin dependent and non-insulin dependent vari- eties) has been reported to be increased in Turner syn- drome. Ischemic heart disease, stroke, and hypertension are also more common. Growth in children with Turner syndrome is charac- terized by a slight intrauterine growth retardation, rela- tively normal growth rates for the first several years of life, a progressive deceleration of growth later in child- hood, and the lack of a pubertal growth spurt. Growth patterns of Chinese girls with Turner syndrome parallel those of Caucasians, although their ultimate height is still less than normal. Contrary to earlier reports, most individuals with Turner syndrome are not mentally retarded. They may have some learning disabilities, particularly with regard to spatial perception, visual-motor coordination, and mathematics. As a result, the nonverbal IQ in Turner syn- drome tends to be lower than the verbal IQ. Cardiovascular malformations are well-recognized congenital anomalies in Turner syndrome. Dilation and dissection of the aorta are reported in approximately half of women with Turner syndrome. Because of the poten- tial consequences of aortic dilation, some experts recom- mend screening all individuals with Turner syndrome. However, the specific timing for this screening remains controversial in 2001. Juvenile arthritis, an autoimmune condition, has been recently (1998) associated with Turner syndrome. The prevalence seems to be at least six times greater than would be expected if the two conditions were only ran- domly associated. Women with Turner syndrome have an GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1155 Turner syndrome KEY TERMS Chromosome—A microscopic thread-like struc- ture found within each cell of the body that con- sists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromo- somes or their shape and size (structure) may lead to physical or mental abnormalities. Mosaic—A term referring to a genetic situation in which an individual’s cells do not have the exact same composition of chromosomes. In Down syn- drome, this may mean that some of the individ- ual’s cells have a normal 46 chromosomes, while other cells have an abnormal 47 chromosomes. Ovary—The female reproductive organ that pro- duces the reproductive cell (ovum) and female hormones. Zygote—The cell formed by the uniting of egg and sperm. elevated prevalence rate of dental caries and other peri- odontal conditions such as gum disease and plaque. Normal pubertal development and spontaneous men- strual periods do not occur in the majority of children with Turner syndrome. It is estimated that 3-8% of girls with a single X chromosome and 12-21% of females with sex chromosome mosaicism may have normal pubertal development and spontaneous menstrual periods. A few pregnancies have been reported in women with Turner syndrome. Diagnosis Turner syndrome is diagnosed on the basis of genetic analysis of chromosomes. This can be done prior to birth. However, the predictive value of amniocentesis in diag- nosing Turner syndrome varies from 21-67%. There is no significant relation between mother’s age and risk of Turner syndrome. Treatment and management Because it is so dangerous, experts suggest screening for aortic dissection, although the specific timing for this screening is controversial. Plastic surgery to correct web- bing of the neck should be considered at an early age (before entering school) for girls with Turner syndrome. Most individuals with Turner syndrome require female hormone therapy to promote development of sec- ondary sexual characteristics and menstruation. The time of beginning therapy varies with individuals. Experts rec- ommend that therapy begin when a woman expresses concern about her onset of puberty. All women receiving long term, exogenous female hormone therapy require periodic gynecological exami- nations because those with Turner syndrome have an increased risk of developing neoplasms such as gonadoblastoma and dysgerminoma, which arise from their rudimentary streak gonads. Prognosis Most women with Turner syndrome can live rela- tively normal lives. The prognosis for people with Turner syndrome is dependent on other conditions that may be present. Care must be taken to regularly monitor them for the health problems that are associated with Turner syn- drome. For example, heart or kidney defects, hearing loss, or the development of inflammatory bowel disease may significantly impact the quality of life. Without these types of conditions, however, their life expectancy is nor- mal. Support will be necessary to help an adolescent girl cope with body image issues and to help some women accept the fact that they will never be able to have chil- dren. Resources BOOKS Hall, Judith G. “Chromosomal Clinical Abnormalities.” In Nelson Textbook of Pediatrics, edited by Richard E. Behrman, et al. 16th ed. Philadelphia: W.B. Saunders, 2000, pp. 325-334. Jones, K.L. “XO Syndrome.” In Smith’s Recognizable Patterns of Human Malformation. Edited by Kenneth L. Jones and Judy Fletcher. 5th ed. Philadelphia: W.B. Saunders, 1997, pp. 81-87. Plumridge, D. Good Things Come in Small Packages: The Whys and Hows of Turner Syndrome. Portland, OR: University of Oregon Health Sciences Center, 1987. Reiser, P.A., and L.E. Underwood. Turner Syndrome: A Guide for Families. Wayzata, MN: Turner Syndrome Society, 1992. PERIODICALS Gravholt, C.H., et al. “Morbidity in Turner Syndrome.” Journal of Clinical Epidemiology 51, no. 2 (February 1998): 147- 158. Gravholt, C.H., et al. “Prenatal and Postnatal Prevalence of Turner’s Syndrome: A Registry Study.” British Medical Journal 312, no. 7022 (January 6, 1996): 16-21. Zinn, A.R., D.C. Page, and E.M. Fisher. “Turner Syndrome: The Case of the Missing Sex Chromosome.” Trends in Genetics 9 (1993): 90-93. ORGANIZATIONS American Academy of Pediatrics. 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098. (847) 434-4000. Fax: (847) 434-8000. Ͻhttp://www.aap.org/visit/contact.htmϾ. Endocrine Society. 4350 East West Highway, Suite 500, Bethesda, MD 20814-4410. (301) 941-0200. Fax: (301) 941-0259. endostaff@endo-society.org. 1156 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Turner syndrome Females with Turner syndrome usually have a short neck with characteristic skin folds such as that shown here. (Custom Medical Stock Photo, Inc.) Human Growth Foundation. 997 Glen Cove Ave., Glen Head, NY 11545. (800) 451-6434. Fax: (516) 671-4055. Ͻhttp://www. hgf1@hgfound.orgϾ. MAGIC Foundation for Children’s Growth. 1327 N. Harlem Ave., Oak Park, IL 60302. (708) 383-0808 or (800) 362- 4423. Fax: (708) 383-0899. mary@magicfoundation.org. Ͻhttp://www.magicfoundation.org/ghd.htmlϾ. Turner Syndrome Society of Canada. 7777 Keele St, Floor 2, Concord, ONT L4K 1Y7. Canada (800) 465-6744 or (416) 660-7766. Fax: (416) 660-7450. Turner Syndrome Society of England. 2 Mayfield Ave., London, W41PW. UK 44 (0)181-994 7625. Fax: 44 (0)181-995 9075. Ͻhttp://www.exnet.com/staff/sys4/ts .htmlϾ or Ͻhttp://www.tss.org.ukϾ. Turner Syndrome Society of the United States. 14450 T. C. Jester, Suite 260, Houston, TX 77014. (800) 365-9944 or (832) 249-9988. Fax: (832) 249-9987. tesch@turner- syndrome-us.org. Ͻhttp://www.turner-syndrome-us.orgϾ. WEBSITES American Academy of Pediatrics. Ͻhttp://www.aap.org/visit/contact.htmϾ. On-ramp Access. Ͻhttp://www.onr.com/ts-texas/turner.htmlϾ. Turner Syndrome Support Society (UK). Ͻhttp://www.tss.org.uk/Ͼ. University of Kansas Medical Center. Ͻhttp://www.kumc.edu/gec/support/turner.htmlϾ. L. Fleming Fallon, Jr., MD, PhD, DrPH Twin reversed arterial perfusion syndrome see Acardia Twiner-Kieser syndrome see Nail-Patella syndrome Type I diabetes see Diabetes mellitus Type II diabetes see Diabetes mellitus Typical arthrogryposis see Distal arthrogryposis syndrome GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1157 Turner syndrome I Urea cycle disorders Definition Urea cycle disorders are inborn errors in metabolism that can lead to brain damage and death. They involve a deficiency in one of the enzymes required by the urea cycle that removes ammonia from the blood. Description Ammonia accumulates in toxic levels if the urea cycle does not convert nitrogen from protein metabolism into urea for excretion into the urine. A series of bio- chemical reactions are necessary to complete the urea cycle. When an enzyme is missing or deficient, the cycle is interrupted and nitrogen accumulates in the form of ammonia. It cannot be excreted from the body and enters the blood stream, damaging nervous tissues, including the brain. Seizures, poor muscle tone, respiratory distress, and coma follow if an affected infant is not treated. Acute neonatal symptoms are most frequently seen in boys with ornithine transcarbamylase, or OTC, deficiency. Mental retardation and even death may follow. People with par- tial deficiencies may not discover the problem until childhood or adulthood. Children may avoid meat or other protein foods. As ammonia levels rise in the body, individuals begin to show lethargy and delirium. Left untreated they may suffer a coma or death. Sometimes young people with urea cycle disorders, who go undiagnosed, begin to show behavioral and eat- ing problems. Those with partial enzyme deficiencies may experience episodes of high ammonia levels in the blood. This can occur after suffering from viral illnesses including chicken pox, or after eating high-protein meals, or even after significant physical exertion. The incidence of adults with urea cycle disorders is increasing. Recent evidence has indicated that some peo- ple have survived undiagnosed into adulthood. They can suffer stroke-like symptoms, lethargy, and delirium. Without proper diagnosis and treatment, adults are at risk for permanent brain damage, coma, and death. Symptoms can appear after giving birth or after contract- ing a virus, and some adults have shown deficiencies after using the medication valproic acid (an anti-epileptic drug). Adult onset is more common in women with OTC deficiency. Different enzymes may be lacking in the various forms of urea cycle disorders. The six major disorders of the urea cycle include: • CPS–Carbamyl Phosphate Synthetase • NAGS–N-Acetylglutamate Synthetase • OTC–Ornithine Transcarbamylase • ASD–Argininosuccinic Acid Synthetase (Citrulli- nemia) • ALD–Argininosuccinase Acid Lyase (Argininosuccinic Aciduria) • AG–Arginase Genetic profile All of these disorders are inherited as autosomal recessive traits except for ornithine transcarbamylase (OTC) deficiency. It is inherited as an X-linked trait, from the mother. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1159 U KEY TERMS Enzyme—A protein that catalyzes a biochemical reaction or change without changing its own structure or function. Urea cycle—A series of complex biochemical reactions that remove nitrogen from the blood so ammonia does not accumulate. Demographics It is estimated the incidence of urea cycle disorders is about one in 30,000 births. Males and females are affected equally, except for the OTC deficiency which is more prevalent in males due to the fact that it is an X- linked disorder. Signs and symptoms In severe urea cycle disorders, rising ammonia levels cause irritability, vomiting, and lethargy within the first 24–72 hours of life. Seizures, poor muscle tone, respira- tory distress, and coma follow if the infant is not treated. Acute neonatal symptoms are most frequently seen in boys with ornithine transcarbamylase, or OTC, defi- ciency. However, patients with mild or moderate urea cycle enzyme deficiencies may not show symptoms until early childhood. Diagnosis Early detection through blood testing is essential to prevent irreversible brain damage in severe cases of urea cycle disorders. Treatment and management Therapy consists of eating a diet that provides enough protein so the body gets the essential amino acids needed for growth, but not so much that toxic levels of ammonia are formed. Treatment may entail a protein restricted diet together with medications that provide alternative pathways for the removal of ammonia from the blood. These medications tend to be unpalatable and may be given by way of tube feedings. Blood tests are needed to monitor levels of ammonia, and hospitaliza- tions may become necessary if levels rise to high. Prognosis With early detection and proper diet restrictions, individuals can lead relatively normal lives. However, irreversible brain damage can develop quickly in severe cases that go undetected. Resources 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. Ͻhttp://www .rarediseases.orgϾ. National Urea Cycle Disorders Foundation. 4841 Hill St., La Canada, CA 91001. (800) 38-NUCDF. Julianne Remington I Usher syndrome Definition Usher syndrome is an inherited condition that causes hearing loss and a form of vision loss, called retinitis pigmentosa (RP), which worsens over time. Some peo- ple with Usher syndrome also have difficulties with bal- ance and/or psychological problems. Although the symptoms of Usher syndrome were first described in 1858 by an ophthalmologist named Albrecht von Graefe, it was not until 1914 that it was well documented and rec- ognized to be a genetic condition by another ophthalmol- ogist, Charles Usher. There are three forms of Usher syndrome: type I, type II, and type III. Genetic research has shown there are many genes located on different chromosomes, all of which can lead to one of the types of Usher syndrome if they are altered. Description Usher syndrome is sometimes called hereditary deafness–retinitis pigmentosa, or retinitis pigmentosa and congenital deafness. Usher syndrome causes a spe- cific type of hearing impairment called sensorineural hearing loss (SNHL). In order to understand how SNHL occurs, it is important to first understand how normal hearing works. 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 por- tion of the ear), the ear canal, and 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 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 mes- sages 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 special- ized 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 1160 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Usher syndrome 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 envi- ronment is quiet. People with severe hearing loss (66-85 dB) have difficulty hearing conversation unless the speaker is nearby or is talking loudly. Profound hearing loss (Ͼ85 dB) may prevent people from hearing sounds from their environment or even loud conversation. People with Usher syndrome generally have moderate, severe or profound SNHL, depending upon the type (I, II, or III) diagnosed. Usher syndrome also causes a specific type of vision loss called retinitis pigmentosa (RP). In order to under- stand how RP occurs, it is helpful to first understand how normal vision works. The eye is made up of many differ- ent types of cells and tissues that all work together to send images from the environment to the brain, similar to the way a camera records images. When light enters the eye, it passes through the lens and lands on the retina, a very thin tissue lining the inside of the eye. The retina is actually made up of 10 different layers of specialized cells, which allow the retina to function similarly to film in a camera, by recording images. There is a small, yel- low-pigmented area called the macula, located in the back of the eye in the center of the retina. The retina con- tains many specialized cells called photoreceptors, which sense light coming into the eye and convert it into elec- trical messages that are then sent to the brain through the optic nerve. This allows the brain to “see” the environ- ment. The retina contains two types of photoreceptor cells: rod cells and cone cells. Rod cells are located primarily outside of the macula and they allow for peripheral (side) and night vision. Most of the photoreceptor cells inside of the macula, however, are the cone cells, which are responsible for perceiving color and for viewing objects directly in front of the eye (central vision). If the retina is diseased, as in RP, night vision and peripheral vision are altered. This happens in RP because the rod and cone cells degenerate (breakdown) and die over time, resulting in night blindness and decreased peripheral vision (also called “tunnel vision”). People with Usher syndrome develop RP at different ages depending upon the type (I, GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1161 Usher Syndrome KEY TERMS Central vision—The ability to see objects located directly in front of the eye. Central vision is neces- sary for reading and other activities that require people to focus on objects directly in front of them. Cochlea—A bony structure shaped like a snail shell located in the inner ear. It is responsible for chang- ing sound waves from the environment into electri- cal messages that the brain can understand, so people can hear. Genetic heterogeneity—The occurrence of the same or similar disease, caused by different genes among different families. Peripheral vision—The ability to see objects that are not located directly in front of the eye. Peripheral vision allows people to see objects located on the side or edge of their field of vision. Photoreceptors—Specialized cells lining the inner- most layer of the eye that convert light into electri- cal messages so that the brain can perceive the environment. There are two types of photoreceptor cells: rod cells and cone cells. The rod cells allow for peripheral and night vision. Cone cells are responsible for perceiving color and for central vision. Retina—The light-sensitive layer of tissue in the back of the eye that receives and transmits visual signals to the brain through the optic nerve. Retinitis pigmentosa—Progressive deterioration of the retina, often leading to vision loss and blind- ness. Sensorineural hearing loss (SNHL)—Hearing loss that occurs when parts of the inner ear, such as the cochlea and/or auditory nerve, do not work cor- rectly. It is often defined as mild, moderate, severe, or profound, depending upon how much sound can be heard by the affected individual. Vestibular system—A complex organ located inside the inner ear that sends messages to the brain about movement and body position. It allows people to maintain their balance when moving by sensing changes in their direction and speed. [...]... lissencephaly.orgϾ National Hydrocephalus Foundation 124 13 Centralia, Lakewood, CA 9071 5-1 623 (5 62) 4 0 2- 3 523 or (88 8) 26 01 789 hydrobrat@earthlink.net Ͻhttp://www.nhfonline orgϾ National Organization for Rare Disorders (NORD) PO Box 8 923 , New Fairfield, CT 0 68 1 2- 8 923 (20 3) 74 6-6 5 18 or (80 0) 99 9-6 673 Fax: (20 3) 74 6-6 481 Ͻhttp://www rarediseases.orgϾ WEBSITES “Fukuyama Congenital Muscular Dystrophy.” OMIM–Online... Medicine (July 20 00): 107–110 ORGANIZATIONS Alexander Graham Bell Association for the Deaf, Inc 3417 Volta Place NW, Washington, DC 20 007 -2 7 78 (80 0) 4 327 543 Ͻhttp://www.agbell.orgϾ FACES: The National Craniofacial Association PO Box 110 82 , Chattanooga, TN 37401 ( 423 ) 26 6-1 6 32 or (80 0) 3 322 373 faces@faces-cranio.org Ͻhttp://www.faces-cranio org/Ͼ National Association of the Deaf 81 4 Thayer, Suite 25 0, Silver... Medical Journal 723 5 (March 4, 20 00): 622 - 626 ORGANIZATIONS American Council of the Blind 1155 15th St NW, Suite 720 , Washington, DC 20 005 (20 2) 46 7-5 081 or (80 0) 424 86 66 Ͻhttp://www.acb.orgϾ Boys Town National Research Hospital 555 N 30th St., Omaha, NE 681 31 (4 02) 49 8- 6 749 Ͻhttp://www boystown.org/Btnrh/Index.htmϾ DB-LINK, Teaching Research 345 N Monmouth Ave., Monmouth, OR 97361 (80 0) 43 8- 9 376 Ͻhttp://www.tr... PO Box 4 58, Crystal Lake, IL 60014 (3 12) 33 7-0 7 42 or (88 8) 48 6- 120 9 aboutface2000@aol.com Ͻhttp://www.aboutface2000.orgϾ Family Village Waisman Center, University of WisconsinMadison, 1500 Highland Ave., Madison, WI 53705 -2 2 80 familyvillage@waisman.wisc.edu Ͻhttp://www.familyvillage.wisc.edu/index.htmlϾ WideSmiles PO Box 5153, Stockton, CA 9 520 5-0 153 (20 9) 9 4 2- 28 12 Ͻhttp://www.widesmiles.orgϾ Cindy L... Deaf 81 4 Thayer, Suite 25 0, Silver Spring, MD 20 91 0-4 500 (301) 58 7-1 788 nadinfo@nad org Ͻhttp://www.nad.orgϾ National Organization for Albinism and Hypopigmentation 1530 Locust St #29 , Philadelphia, PA 191 0 2- 4415 (21 5) 545 -2 3 22 or (80 0) 473 -2 3 10 Ͻhttp://www.albinism orgϾ Research Registry for Hereditary Hearing Loss 555 N 30th St., Omaha, NE 681 31 (80 0) 320 -1 171 Ͻhttp://www boystown.org/btnrh/deafgene.reg/waardsx.htmϾ... House, 385 Euston Road, London, NW1 3AU UK 0171 380 0600 Fax: 0171 387 82 2 0 melissa @haemophilia-soc.demon.co.uk Ͻhttp://www.haemophiliasoc.demon.co.uk/vwd %20 services1.htmlϾ National Hemophilia Foundation Soho Building, 110 Greene Street, Suite 406, New York, NY 100 12 (21 2) 21 9 -8 180 Ͻhttp://www.hemophilia.org/home.htmϾ OTHER Mannucci, Pier “Desmopressin (DDAVP) in the Treatment of Bleeding Disorders: The. .. British Dental Journal 188 , no 2 (January 22 , 20 00): 78 83 VATER association KEY TERMS Anus The opening at the end of the intestine that carries waste out of the body Fistula—An abnormal passage or communication between two different organs or surfaces Genetic profile The exact genetic cause of VATER association is unknown Most cases are sporadic and do not occur more than once in the same family This... angioma dx = Diagnosed dx.42y d.44y d.75y 59y dx.32y d.45y 53y 70y d.39y +Epididymal cystadenoma 46y dx . 28 y 2 31y dx . 28 y 28 y 26 y dx .25 y 29 y 22 y 15y (Gale Group) VHL is caused by a change or mutation in the VHL gene This gene is located on chromosome 3 and produces the VHL protein The VHL protein is a tumor suppressor, meaning that it controls cell growth When the VHL gene is changed, the VHL protein does... 11 78 Skin hematoma—Blood from a broken blood vessel that has accumulated under the skin Genetic profile The genetics of VWD are complex and involve a gene that produces vWF and is found on chromosome 12 Since two of each type of chromosome are inherited, children inherit two vWF genes There are different types of changes in the vWF gene that can affect the production GALE ENCYCLOPEDIA OF GENETIC DISORDERS. .. 80 0, 11350 McCormick Rd., Hunt Valley, MD 21 031 (88 8) 39 4-3 937 Ͻhttp://www.blindness.orgϾ Helen Keller National Center for Deaf-Blind Youths and Adults 111 Middle Neck Rd., Sands Point, NY 11050 (516) 94 489 00 Ͻhttp://www.helenkeller.org/national/index.htmϾ Usher Family Support 49 18 42nd Ave South, Minneapolis, MN 55417 (6 12) 724 -6 9 82 Vestibular Disorders Association PO Box 4467, Portland, OR 9 720 8- 4 467 . Society of the United States. 14450 T. C. Jester, Suite 26 0, Houston, TX 77014. (80 0) 36 5-9 944 or (8 32) 24 9-9 988 . Fax: (8 32) 24 9-9 987 . tesch@turner- syndrome-us.org. Ͻhttp://www.turner-syndrome-us.orgϾ. WEBSITES American. Organization for Rare Disorders (NORD). PO Box 8 923 , New Fairfield, CT 0 68 1 2- 8 923 . (20 3) 74 6-6 5 18 or (80 0) 99 9-6 673. Fax: (20 3) 74 6-6 481 . Ͻhttp://www .rarediseases.orgϾ. National Urea Cycle Disorders Foundation Ͻhttp://www.helenkeller.org/national/index.htmϾ. Usher Family Support. 49 18 42nd Ave. South, Minneapolis, MN 55417. (6 12) 724 -6 9 82 . Vestibular Disorders Association. PO Box 4467, Portland, OR 9 720 8- 4 467. (80 0) 83 7 -8 4 28 . Ͻhttp://www.vestibular.orgϾ. WEBSITES Sense