The Gale Genetic Disorders of encyclopedia vol 1 - part 10 ppsx

longed QT interval. Genetic testing for JLNS is possi- ble for high-risk individuals. Individuals with JLNS sometimes have normal or borderline-normal QT intervals on an ECG/EKG. Additional ECGs/EKGs performed during exercise may reveal an abnormal QT interval. ECGs/EKGs of the parents may also reveal a prolonged QT interval. Treatment and management Since JLNS can result in sudden death, including sudden infant death syndrome (SIDS), treatment is essen- tial. Beta-blockers are the most common treatment for the ventricular arrhythmia of JLNS. Treatment with these drugs usually continues for life. Beta-blockers such as propranolol are considered to be safe medications. Any side effects from propranolol are usually mild and disap- pear once the body has adjusted to the drug. However, beta-blockers can interact dangerously with many other medications. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 619 Jervell and Lange-Nielsen syndrome KEY TERMS Action potential—The wave-like change in the electrical properties of a cell membrane, resulting from the difference in electrical charge between the inside and outside of the membrane. Arrhythmia—Abnormal heart rhythm, examples are a slow, fast, or irregular heart rate. Autosomal recessive—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease. Beta-adrenergic blocker—A drug that works by controlling the nerve impulses along specific nerve pathways. 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 electrical messages that the brain can understand, so people can hear. Congenital—Refers to a disorder which is present at birth. Depolarization—The dissipation of an electrical charge through a membrane. Electrocardiogram (ECG, EKG)—A test used to measure electrical impulses coming from the heart in order to gain information about its structure or function. Endolymph—The fluid in the inner ear. Fibrillation—A rapid, irregular heartbeat. Heterozygous—Having two different versions of the same gene. Homeostasis—A state of physiological balance. Homozygous—Having two identical copies of a gene or chromosome. Ion channel—Cell membrane proteins which control the movement of ions into and out of a cell. QT interval—The section on an electrocardiogram between the start of the QRS complex and the end of the T wave, representing the firing or depolarization of the ventricles and the period of recovery prior to repolarization or recharging for the next contraction. Repolarization—Period when the heart cells are at rest, preparing for the next wave of electrical cur- rent (depolarization). Syncope—A brief loss of consciousness caused by insufficient blood flow to the brain. Tachycardia—An excessively rapid heartbeat; a heart rate above 100 beats per minute. Torsade de pointes—A type of tachycardia of the ventricles characteristic of Jervell and Lange- Nielsen syndrome. Signs and symptoms The deafness associated with JLNS usually is apparent in infancy or early childhood. Although the severity of JLNS varies, children with acute JLNS are profoundly deaf in both ears. Depending on the severity of the disorder, the cardiac symptoms of JLNS may be overlooked. Thus, people with JLNS can be at serious risk for sudden death. In addition to a prolonged QT interval on an ECG/EKG, cardiac arrhythmias, dizziness, periods of unconscious- ness (syncopic episodes), and seizures are common symptoms of JLNS. These symptoms most often occur upon awakening, during strenuous physical activity, or during moments of excitement or stress. Diagnosis Deaf children, particularly those with a family history of sudden death, syncopic episodes, or LQTS should be screened for JLNS, using an ECG to detect a pro- Surgery may reduce cardiac arrhythmias in people with JLNS. A mechanical device called a pacemaker or an automatic implanted cardioverter defibrillator (AICD) may be used to regulate the heartbeat or to detect and cor- rect abnormal heart rhythms. Sometimes a pacemaker or AICD is used in combination with beta-blockers. In 2000, the first cochlear implant in the inner ear of a child with JLNS was reported. The child gained limited hearing and improved speech. Preventative measures All individuals who have been diagnosed with JLNS must avoid reductions in blood potassium levels, such as those that occur with the use of diuretics (drugs that reduce fluids in the body). People with JLNS must also avoid a very long list of drugs and medications that can increase the QT interval or otherwise exacerbate the syndrome. People with JLNS usually are advised to refrain from competitive sports and to practice a “buddy system” during moderate exercise. Family members are advised to learn cardiopulmonary resuscitation (CPR) in case of cardiac arrest. Prognosis Cochlear implants may improve the hearing of people with JLNS. The cardiac abnormalities of JLNS usually can be controlled with beta-blockers. However, without treatment, there is a high incidence of sudden death due to cardiac events. Family members of a JLNS individual should be screened with ECGs/EKGs for a prolonged QT interval, since they are at risk of having LQTS. Genetic counseling is recommended for people with JLNS, since their children will inherit a gene causing LQTS. Resources PERIODICALS Chen, Q., et al. “Homozygous Deletion in KVLQT1 Associated with Jervell and Lange-Nielsen Syndrome.” Circulation 99 (1999): 1344-47. Schmitt, N., et al. “A Recessive C-terminal Jervell and Lange- Nielsen Mutation of the KCNQ1 Channel Impairs Subunit Assembly.” The EMBO Journal 19 (2000): 332-40. Steel, Karen P. “The Benefits of Recycling.” Science 285 (August 27, 1999): 1363-1364. ORGANIZATIONS American Heart Association. 7272 Greenville Ave., Dallas, TX 75231-4596. (214) 373-6300 or (800) 242-8721. inquire @heart.org. Ͻhttp://www.americanheart.orgϾ. American Society for Deaf Children. PO Box 3355, Gettysburg, PA 17325. (800) 942-ASDC or (717) 334- 7922 v/tty. Ͻhttp://www.deafchildren.org/asdc2k/home/ home.shtmlϾ. Deafness Research Foundation. 575 Fifth Ave., 11th Floor, New York, NY 10017. (800) 535-3323. drf@drf.org. EAR (Education and Auditory Research) Foundation. 1817 Patterson St., Nashville, TN 37203. (800) 545-HEAR. earfound@earfoundation.org. Ͻhttp://www.theearfound .orgϾ. European Long QT Syndrome Information Center. Ronnerweg 2, Nidau, 2560. Switzerland 04(132) 331-5835. jmet- tler@bielnews.ch. Ͻhttp://www.bielnews.ch/cyberhouse/ qt/qt.htmlϾ. Sudden Arrhythmia Death Syndrome Foundation. PO Box 58767, 508 East South Temple, Suite 20, Salt Lake City, UT 84102. (800) 786-7723. sads@sads.org. Ͻhttp://www .sads.orgϾ. WEBSITES Contie, Victoria L. “Genetic Findings Help Tame the Runaway Heart.” NCAA Reporter. Ͻhttp://www.ncrr.nih.gov/ newspub/ nov97rpt/heart.htmϾ (November-December 1997). “Genetics of Long QT Syndrome/Cardiac Arrest.” DNA Sciences. Ͻhttp://my.webmd.com/content/article/3204.676Ͼ (2001). Long QT Syndrome European Information Center. Ͻhttp:// www.qtsyndrome.ch/lqts.htmlϾ Narchi, Hassib, and Walter W. Tunnessen Jr. “Denouement and Discussion: Jervell and Lange-Nielsen Syndrome (Long QT Syndrome).” Archives of Pediatrics and Adolescent Medicine, 153 (4). Ͻhttp://archpedi.ama-assn.org/ issues/ v153n4/ffull/ppm8451-1b.htmlϾ (April 1999). Margaret Alic, PhD I Joubert syndrome Definition Joubert syndrome is a well documented but rare autosomal recessive disorder. The syndrome is characterized by partial or complete absence of the cerebellar vermis (the connective tissue between the two brain hemisperes), causing irregular breathing and severe muscle weakness. Other features of the syndrome include jerky eye movements, abnormal balance and walking, and mental handicap. There may be minor birth defects of the face, hands, and feet. Description Marie Joubert (whose name is given to the condition) gave a detailed description of the syndrome in 1969. She wrote about four siblings (three brothers, one sister) in one family with abnormal breathing, jerky eye movements (nystagmus), poor mental development, and ataxia 620 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Joubert syndrome (staggering gait and imbalance). X ray examination showed that a particular section of the brain, called the cerebellar vermis, was absent or not fully formed. This specific brain defect was confirmed on autopsy in one of these individuals. Her initial report also described a sporadic (non-inherited) patient with similar findings, in addition to polydactyly. Another name for Joubert syndrome is Joubert-Bolthauser syndrome. Genetic profile There have been numerous instances of siblings (brothers and sisters), each with Joubert syndrome. The parents were normal. A few families have also been seen where the parents were said to be closely related (i.e. may have shared the same altered gene within the family). For these reasons, Joubert syndrome is an autosomal recessive disorder. Autosomal means that both males and females can have the condition. Recessive means that both parents would be carriers of a single copy of the responsible gene. Autosomal recessive disorders occur when a person inherits a particular pair of genes that do not work cor- rectly. The chance that this would happen to children of carrier parents is 25% (1 in 4) for each pregnancy. It is known that the cerebellum and brain stem begin to form between the sixth and twelfth week of pregnancy. The birth defects seen in Joubert syndrome must occur during this crucial period of development. As of 2001, the genetic cause remains unknown. Demographics Joubert syndrome affects both males and females, although more males (ratio of 2:1) have been reported with the condition. The reason why more males have the condition remains unknown. Joubert syndrome is found worldwide, with reports of individuals of French Canadian, Swedish, German, Swiss, Spanish, Dutch, Italian, Indian, Belgian, Laotian, Moroccan, Algerian, Turkish, Japanese, and Portuguese origin. In all, more than 200 individuals have been described with Joubert syndrome. Signs and symptoms The cerebellum is the second largest part of the brain. It is located just below the cerebrum, and partially covered by it. The cerebellum consists of two hemispheres, separated by a central section called the vermis. The cerebellum is connected to the spinal cord, through the brain stem. The cerebellum (and vermis) normally works to monitor and control movement of the limbs, trunk, head, GALE ENCYCLOPEDIA OF GENETIC DISORDERS 621 Joubert syndrome KEY TERMS Apnea—An irregular breathing pattern characterized by abnormally long periods of the complete cessation of breathing. Ataxia—A deficiency of muscular coordination, especially when voluntary movements are attempted, such as grasping or walking. Cerebellum—A portion of the brain consisting of two cerebellar hemispheres connected by a nar- row vermis. The cerebellum is involved in control of skeletal muscles and plays an important role in the coordination of voluntary muscle movement. It interrelates with other areas of the brain to facili- tate a variety of movements, including maintaining proper posture and balance, walking, running, and fine motor skills, such as writing, dressing, and eating. Iris—The colored part of the eye, containing pig- ment and muscle cells that contract and dilate the pupil. Nystagmus—Involuntary, rhythmic movement of the eye. Polydactyly—The presence of extra fingers or toes. 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. Vermis—The central portion of the cerebellum, which divides the two hemispheres. It functions to monitor and control movement of the limbs, trunk, head, and eyes. and eyes. Signals are constantly received from the eyes, ears, muscle, joints, and tendons. Using these signals, the cerebellum is able to compare what movement is actually happening in the body, with what is intended to happen. Then, it sends an appropriate signal back. The effect is to either increase or decrease the function of different muscle groups, to make movement both accurate and smooth. In Joubert syndrome, the cerebellar vermis is either absent or incompletely formed. The brain stem is sometimes quite small. The absence or abnormal function of these brain tissues causes problems in breathing and vision, and severe delays in development. One characteristic feature of Joubert syndrome is the pattern of irregular breathing. Their breathing alter- nates between deep rapid breathing (almost like pant- ing) with periods of severe apnea (loss of breathing). This is usually noticeable at birth. The rate of respira- tion may increase more than three times that of normal (up to 200 breaths per minute) and the apnea may last up to 90 seconds. The rapid breathing occurs most often when the infant is awake, especially when they are aroused or excited. The apnea happens when the infants are awake or asleep. Such abnormal breathing can cause sudden death or coma, and requires that these infants be under intensive care. For unknown reasons, the breathing tends to improve with age, usually within the first year of life. Muscle movement of the eye is also affected in Joubert syndrome. It is common for the eyes to have a quick, jerky motion of the pupil, known as nystagmus. The retina (the tissue in the back of the eye that receives and transmits visual signals to the brain) may be abnormal. Some individuals (most often the males) may have a split in the tissue in the iris of the eye. Each of these problems will affect their vision, and eye surgery may not be beneficial. The central nervous system problem affects the larger muscles of the body as well, such as those for the arms and legs. Many of the infants will have severe muscle weakness and delays in development. They reach normal developmental milestones, such as sitting or walking, much later than normal. For example, some may learn to sit without support by around 19–20 months of age (normal is six to eight months). Most individuals are not able to take their first steps until age four or older. Their balance and coordination are also affected, which makes walking difficult. Many will have an unsteady gait, and find it difficult to climb stairs or run, even as they get older. Cognitive (mental) delays are also a part of the syndrome, although this can be variable. Most individuals with Joubert syndrome will have fairly significant learn- ing impairment. Some individuals will have little or no speech. Others are able to learn words, and can talk with the aid of speech therapy. They do tend to have pleasant and sociable personalities, but problems in behavior can occur. These problems most often are in temperament, hyperactivity, and aggressiveness. Careful examination of the face, especially in infancy, shows a characteristic appearance. They tend to have a large head, and a prominent forehead. The eye- brows look high, and rounded, and the upper eyelids may be droopy (ptosis). Their mouth many times remains open, and looks oval shaped in appearance. The tongue may protrude out of the mouth, and rest on the lower lip. The tongue may also quiver slightly. These are all signs of the underlying brain abnormality and muscle weakness. Occasionally, the ears look low set on the face. As they get older, the features of the face become less noticeable. Less common features of the syndrome include minor birth defects of the hands and feet. Some individuals with Joubert syndrome have extra fingers on each hand. The extra finger is usually on the pinky finger side (polydactyly). It may or may not include bone, and could just be a skin tag. A few of these patients will also have extra toes on their feet. Diagnosis The diagnosis of Joubert syndrome is made on the following features. First, there must be evidence of the cerebellar vermis either being absent or incompletely formed. This can be seen with a CT scan or MRI of the brain. Second, the physician should recognize the infant has both muscle weakness and delays in development. In addition, there may be irregular breathing and abnormal eye movements. Having four of these five criteria is enough to make the diagnosis of Joubert syndrome. Most individuals are diagnosed by one to three years of age. Treatment and management During the first year of life, many of these infants require a respiratory monitor for the irregular breathing. For the physical and mental delays, it becomes necessary 622 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Joubert syndrome This child is diagnosed with Joubert syndrome. Common symptoms of this disorder include mental retardation, poor coordination, pendular eye movement, and abnormal breathing patterns. (Photo Researchers, Inc.) to provide special assistance and anticipatory guidance. Speech, physical, and occupational therapy are needed throughout life. Prognosis The unusual pattern of breathing as newborns, especially the episodes of apnea, can lead to sudden death or coma. A number of individuals with Joubert syndrome have died in the first three years of life. For most individuals, the irregular breathing becomes more normal after the first year. However, many continue to have apnea, and require medical care throughout their life. Although the true lifespan remains unknown, there are some individuals with Joubert syndrome who are in their 30s. Resources ORGANIZATIONS Joubert Syndrome Foundation Corporation. c/o Stephanie Frazer, 384 Devon Drive, Mandeville, LA 70448. OTHER Alliance of Genetic Support Groups. Ͻhttp://www.geneticalliance.org.htmϾ. Joubert Syndrome Foundation Corporation. Ͻhttp://www.joubertfoundation.comϾ. Kevin M. Sweet, MS, CGC GALE ENCYCLOPEDIA OF GENETIC DISORDERS 623 Joubert syndrome I Kabuki syndrome Definition Kabuki syndrome is a rare disorder characterized by unusual facial features, skeletal abnormalities, and intellectual impairment. Abnormalities in different organ systems can also be present, but vary from individual to individual. There is no cure for Kabuki syndrome, and treatment centers on the specific abnormalities, as well as on strategies to improve the overall functioning and quality of life of the affected person. Description Kabuki syndrome is a rare disorder characterized by mental retardation, short stature, unusual facial features, abnormalities of the skeleton and unusual skin ridge patterns on the fingers, toes, palms of the hands and soles of the feet. Many other organ systems can be involved in the syndrome, displaying a wide variety of abnormalities. Thus, the manifestations of Kabuki syndrome can vary widely among different individuals. Kabuki syndrome (also known as Niikawa-Kuroki syndrome) was first described in 1980 by Dr. N. Niikawa and Dr. Y. Kuroki of Japan. The disorder gets its name from the characteristic long eyelid fissures with eversion of the lower eyelids that is similar to the make-up of actors of Kabuki, a traditional Japanese theatrical form. Kabuki syndrome was originally known as Kabuki Make-up syndrome, but the term “make-up” is now often dropped as it is considered offensive to some families. Scientific research conducted over the past two decades suggests that Kabuki syndrome may be associated with a change in the genetic material. However, it is still not known precisely what this genetic change may be and how this change in the genetic material alters growth and development in the womb to cause Kabuki syndrome. Genetic profile As stated above, the etiology of Kabuki syndrome is not completely understood. While Kabuki syndrome is thought to be a genetic syndrome, little or no genetic abnormality has been identified as of yet. Chromosome abnormalities of the X and Y chromosome or chromosome 4 have occurred in only a small number of individuals with Kabuki syndrome, but in most cases, chromosomes are normal. In almost all cases of Kabuki syndrome, there is no family history of the disease. These cases are thought to represent new genetic changes that occur randomly and with no apparent cause and are termed sporadic. However, in several cases the syndrome appears to be inherited from a parent, supporting a role for genetics in the cause of Kabuki syndrome. Scientists hypothesize that an unidentified genetic abnormality that causes Kabuki syndrome is transmitted as an autosomal dominant trait. With an autosomal dominant trait, only one abnormal gene in a gene pair is necessary to display the disease, and an affected individual has a 50% chance of transmitting the gene and the disease to a child. Demographics Kabuki syndrome is a rare disorder with less than 200 known cases worldwide, but the prevalence of the disease may be underestimated as only a handful of physicians have first-hand experience diagnosing children with Kabuki syndrome. Kabuki syndrome appears to be found equally in males and females. Earlier cases were reported in Japanese children but the syndrome is now known to affect other racial and ethnic groups. Theoretical mathematical models predict that the incidence of Kabuki syndrome in the Japanese popula- tion may be as high as one in 32,000. Signs and symptoms The signs and symptoms associated with Kabuki syndrome are divided into cardinal symptoms (i.e. those GALE ENCYCLOPEDIA OF GENETIC DISORDERS 625 K For children with heart defects, surgical repair is often necessary. This may take place shortly after birth if the heart abnormality is life threatening, but often physicians will prefer to attempt a repair once the child has grown older and the heart is more mature. For children who experience seizures, lifelong treatment with anti- seizure medications is often necessary. Children with Kabuki syndrome often have difficul- ties feeding, either because of mouth abnormalities or because of poor digestion. In some cases, a tube that enters into the stomach, is placed surgically in the abdomen and specially designed nutritional liquids are administered through the tube directly into the stomach. People with Kabuki syndrome are at higher risk for a variety of infections, most often involving the ears and the lungs. In cases such as these, antibiotics are given to treat the infection, and occasionally brief hospital stays are necessary. Most children recover from these infections with proper treatment. Nearly half of people affected by Kabuki syndrome have some degree of hearing loss. In these individuals, formal hearing testing is recommended to determine if they might benefit from a hearing-aid device. A hearing aid is a small mechanical device that sits behind the ear and amplifies sound into the ear of the affected individual. Occasionally, hearing loss in individuals with Kabuki syndrome is severe, approaching total hearing loss. In these cases, early and formal education using American Sign Language as well as involvement with the hearing-impaired community, schools, and enrichment programs is appropriate. Children with Kabuki syndrome should be seen reg- ularly by a team of health care professionals, including a primary care provider, medical geneticist familiar with the condition, gastroenterologist, and neurologist. After growth development is advanced enough (usually late adolescence or early adulthood), consultation with a reconstructive surgeon may be of use to repair physical abnormalities that are particularly debilitating. During early development and progressing into young adulthood, children with Kabuki syndrome should be educated and trained in behavioral and mechanical methods to adapt to any disabilities. This program is usually initiated and overseen by a team of health care professionals including a pediatrician, physical therapist, and occupational therapist. A counselor specially trained to deal with issues of disabilities in children is often helpful is assessing problem areas and encouraging healthy development of self-esteem. Support groups and community organizations for people with disabilities often prove useful to the affected individuals and their families, and specially equipped 626 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Kabuki syndrome KEY TERMS Autosomal dominant—A pattern of genetic inheritance where only one abnormal gene is needed to display the trait or disease. Cardinal symptoms—A group of symptoms that define a disorder or disease. Gastric tube—A tube that is surgically placed though the skin of the abdomen to the stomach so that feeding with nutritional liquid mixtures can be accomplished. Gastroenterologist—A physician who specializes in disorders of the digestive system. Kabuki—Traditional Japanese popular drama performed with highly stylized singing and dancing using special makeup and cultural clothing. Neurologist—A physician who specializes in disorders of the nervous system, including the brain, spine, and nerves. that are almost always present) and variable symptoms (those that may or may not be present). The cardinal and variable signs and symptoms of Kabuki syndrome are summarized in the table below. Diagnosis The diagnosis of Kabuki syndrome relies on physical exam by a physician familiar with the condition and by radiographic evaluation, such as the use of x rays or ultrasound to define abnormal or missing structures that are consistent with the criteria for the condition (as described above). A person can be diagnosed with Kabuki syndrome if they possess characteristics consistent with the five different groups of cardinal symptoms: typical face, skin-surface abnormalities, skeletal abnormalities, mild to moderate mental retardation, and short stature. Although a diagnosis may be made as a newborn, most often the features do not become fully evident until early childhood. There is no laboratory blood or genetic test that can be used to identify people with Kabuki syndrome. Treatment and management There is no cure for Kabuki syndrome. Treatment of the syndrome is variable and centers on correcting the different manifestations of the condition and on strategies to improve the overall functioning and quality of life of the affected individual. enrichment programs should be sought. Further, because many children with Kabuki syndrome have poor speech development, a consultation and regular session with a speech therapist is appropriate. Prognosis The abilities of children with Kabuki syndrome vary greatly. Most children with the condition have a mild to moderate intellectual impairment. Some children will be able to follow a regular education curriculum, while others will require adaptations or modifications to their schoolwork. Many older children may learn to read at a functional level. The prognosis of children with Kabuki syndrome depends on the severity of the symptoms and the extent to which the appropriate treatments are available. Most of the medical issues regarding heart, kidney or intes- tinal abnormalities arise early in the child’s life and are improved with medical treatment. Since Kabuki syndrome was discovered relatively recently, very little is known regarding the average life span of individuals affected with the condition, however, present data on Kabuki syndrome does not point to a shortened life span. Resources BOOKS Behrman, R.E., ed. Nelson Textbook of Pediatrics. Philadelphia: W.B. Saunders, 2000. PERIODICALS Kawame, H. “Phenotypic Spectrum and Management Issues in Kabuki Syndrome.” Journal of Pediatrics 134(April 1999): 480-485. Mhanni, A.A., and A.E. Chudley. “Genetic Landmarks Through Philately—Kabuki Theater and Kabuki Syndrome.” Clinical Genetics 56(August 1999): 116-117. ORGANIZATIONS CardioFacioCutaneous Support Network. 157 Alder Ave., McKee City, NJ 08232. (609) 646-5606. Kabuki Syndrome Network. 168 Newshaw Lane, Hadfield, Glossop, SK13 2AY. UK 01457 860110. Ͻhttp://www .ksn-support.org.ukϾ. 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. WEBSITES “Entry 147920: Kabuki Syndrome.” OMIM—Online Mendelian Inheritance in Man. Ͻhttp://www.ncbi.nlm.nih.gov/ entrez/dispomim.cgi?idϭ147920Ͼ. Oren Traub, MD, PhD I Kallmann syndrome Definition Kallmann syndrome is a disorder of hypogonadotropic hypogonadism, delayed puberty, and anosmia. Description Hypogonadotropic hypogonadism (HH) occurs when the body does not produce enough of two important hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH). This results in underdeveloped gonads and often infertility. Anosmia, the inability to smell, was first described with hypogonadotropic hypogonadism in 1856, but it was not until 1944 that Kallmann reported the inheritance of the two symptoms together in three separate families. Hence, the syndrome of hypogonadotropic hypogonadism and anosmia was named Kallmann syndrome (KS). Kallmann syndrome (KS) is occasionally called dys- plasia olfactogenitalis of DeMorsier. Affected people usually are detected in adolescence when they do not undergo puberty. The most common features are HH and anosmia, though a wide range of features can present in an affected person. Other features of KS may include a small penis or undescended testicles in males, kidney abnormalities, cleft lip and/or palate, clubfoot, hearing problems, and central nervous system problems such as synkinesia, eye movement abnormalities, and visual and hearing defects. Genetic profile Most cases of Kallmann syndrome are sporadic. However, some cases are inherited in an autosomal dominant pattern, an autosomal recessive pattern, or an X- linked recessive pattern. In most cells that make up a person there are structures called chromosomes. Chromosomes contain genes, which are instructions for how a person will grow and develop. There are 46 chromosomes, or 23 pairs of chromosomes, in each cell. The first 22 chromosomes are the same in men and women and are called the autosomes. The last pair, the sex chromosomes, are different in men and women. Men have an X and a Y chromosome (XY). Women have two X-chromosomes (XX). All the genes of the autosomes and the X-chromosomes in women come in pairs. Autosomal dominant inheritance occurs when only one copy of a gene pair is altered or mutated to cause the condition. In autosomal dominant inheritance, the second normal gene copy cannot compensate, or make up for, the altered gene. People with autosomal dominant inheritance have a 50% chance of passing the gene and the condition onto each of their children. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 627 Kallmann syndrome mann syndrome. The gene instructs the body to make a protein called anosmin-1. When this gene is altered in a male, Kallmann syndrome occurs. Of those families who have an X-linked recessive form of KS, approximately 1/2 to 1/3 have identifiable alterations in their KAL gene. Demographics Kallmann syndrome is the most frequent cause of hypogonadotropic hypogonadism and affects approximately 1/10,000 males and 1/50,000 females. Kallmann syndrome is found in all ethnic backgrounds. Because the incidence of KS in males is about five times greater than KS in females, the original belief was that the X-linked form of Kallmann syndrome was the most common. However, as of 2001, it is now assumed that the X-linked recessive form is the least common of all KS. The reason for Kallmann syndrome being more frequent in males is not known. Signs and symptoms Embryology Normally, a structure in the brain called the hypothalamus makes a hormone called gonadotrophin releasing hormone (GnRH). This hormone acts on the pituitary gland, another structure in the brain, to produce the two hormones: follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both of these hormones travel to the gonads where they stimulate the development of sperm in men and eggs in women. FSH is also involved in the release of a single egg from the ovary once a month. Hypogonadotropic hypogonadism results when there is an alteration in this pathway that results in inadequate pro- duction of LH or FSH. In Kallmann syndrome, the alteration is that the hypothalamus is unable to produce GnRH. How hypogonadotropic hypogonadism and the inability to smell are related can be explained during the development of an embryo. The cells that eventually make the GnRH in the hypothalamus are first found in the nasal placode, part of the developing olfactory system (for sense of smell). The GnRH cells must migrate, or move, from the nasal placode up into the brain to the hypothalamus. These GnRH cells migrate by following the path of another type of cell called the olfactory neurons. Neurons are specialized cells that are found in the nervous system and have long tail-like structures called axons. The axons of the olfactory neurons grow from the nasal placode up into the developing front of the brain. Once they reach their final destination in the brain, they form the olfactory bulb, the structure in the brain that helps process odors allowing the sense of smell. The GnRH cells follow the pathway of the olfactory neurons up into the brain to reach the hypothalamus. 628 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Kallmann syndrome KEY TERMS Hormone—A chemical messenger produced by the body that is involved in regulating specific bodily functions such as growth, development, and reproduction. Hypothalamus—A part of the forebrain that con- trols heartbeat, body temperature, thirst, hunger, body temperature and pressure, blood sugar levels, and other functions. Neuron—The fundamental nerve cell that con- ducts impulses across the cell membrane. Pituitary gland—A small gland at the base of the brain responsible for releasing many hormones, including luteinizing hormone (LH) and follicle- stimulating hormone (FSH). Puberty—Point in development when the gonads begin to function and secondary sexual characteristics begin to appear. Synkinesia—Occurs when part of the body will move involuntarily when another part of the body moves. Autosomal recessive inheritance occurs when both copies of a gene are altered or mutated to cause the condition. In autosomal recessive inheritance, the affected person has inherited one altered gene from their mother and the other altered gene from their father. Couples who both have one copy of an altered autosomal recessive gene have a 25% risk with each pregnancy to have an affected child. X-linked recessive inheritance is thought to be the least common form of inheritance in KS, but is the most well understood at the genetic level. With X-linked recessive inheritance, the altered gene that causes the condition is on their X chromosome. Since men have only one copy of the X chromosome, they have only one copy of the genes on the X chromosome. If that one copy is altered, they will have the condition because they do not have a second copy of the gene to compensate. Women, however, can have one altered copy of the gene and not be affected as they have a second copy to compensate. In X-linked recessive conditions, women are generally not affected with the condition. Women who are carriers for an X-linked recessive condition have a 25% chance of having an affected son with each pregnancy. Though all three patterns of inheritance have been suggested for Kallmann syndrome, as of 2001 only one gene has been found that causes Kallmann syndrome. The gene, KAL, is located on the X chromosome and is responsible for most cases of X-linked recessive Kall- In Kallmann syndrome, the olfactory neurons are unable to grow into the brain. Hence, the GnRH cells can not follow their pathway. As a result, the olfactory bulb does not form, resulting in the inability to smell. The GnRH cells can not follow the pathway of the axons and do not reach their final destination in the hypothalamus. Hence, no GnRH is made to stimulate the pituitary to make FSH and LH, resulting in hypogonadotropic hypogonadism. In X-linked recessive KS, the KAL gene instructs the body to make the protein anosmin-1. This protein is involved in providing the pathway in the brain for which the olfactory axons grow. If it is altered in any way, the axons will not know where to grow in the brain and the GnRH cells will be unable to follow. The protein anosmin-1 is also found in other parts of the body, possibly explaining some of the other symptoms sometimes seen in Kallmann syndrome. Other features The features of Kallmann syndrome can vary among affected individuals even within the same family. The two features most often associated with Kallmann syndrome are HH and the inability to smell. Males can also have a small penis and undescended testicles at birth (testicles are still in body and have not dropped down into the scrotal sac). Clubfoot, cleft lip and/or cleft palate can also be present at birth. Clubfoot occurs when one or both feet are not properly placed onto the legs and can appear turned. Cleft lip and/or cleft palate occur when the upper lip and/or the roof of the mouth fail to come together during development. Kidney abnormalities, most often uni- lateral renal agenesis (one kidney did not form) are especially common in those males with X-linked recessive KS. Choanal atresia (pathway from the nose is blocked at birth) and structural heart defects have also been seen in KS. Central nervous system problems can also occur in Kallmann syndrome. These can include nystagmus (involuntary eye movement), ataxia (involuntary body movement), hearing loss and problems with vision. Synkinesia is especially common in men with the X- linked recessive form of KS. Some people with KS are also mentally retarded. Holoprosencephaly, when the brain fails to develop in two halves, can also be seen in some individuals with KS. Diagnosis Individuals with Kallmann syndrome are usually diagnosed when they do not undergo puberty. Hormone testing shows that both LH and FSH are decreased. Affected individuals often do not realize they cannot smell. MRI can often detect the absence of the olfactory bulb in the brain. Renal ultrasound can determine if a kidney is missing. As of 2001, genetic testing for alterations in the KAL gene is the only genetic testing available. Even with families with clear X-linked recessive inheritance, genetic testing does not always detect an alteration in the KAL gene. Hence, diagnosis is still very dependent upon clinical features. Treatment and management When a child with KS is born with structural abnormalities such as cleft lip and/or palate, clubfoot or heart defects, surgery is often required to fix the defect. Taking sex hormones treats delayed puberty; women take estro- gen and men take testosterone. Once puberty is completed, taking GnRH or both LH and FSH can treat hypogonadism. For most affected individuals, treatment is successful and infertility is reversed. However, a small portion of people will not respond to treatment. When an isolated case of Kallmann syndrome is diagnosed, evaluation of first-degree family members, such as parents and siblings, should be completed. This should include a detailed family history, measuring hormone levels, assessing sense of smell, and renal ultrasound to look for kidney abnormalities. This information may help to diagnosis previously unrecognized cases of Kallmann syndrome. Furthermore, this information may be important for genetic counseling and determining whom in the family is at risk for also having Kallmann syndrome. Prognosis For individuals with the most common features of Kallmann syndrome, hypogonadism and the inability to smell, prognosis is excellent. In most cases, hormone treatment is able to reverse the delayed puberty and hypogonadism. For those individuals with other symptoms of Kallmann syndrome, prognosis can depend on how severe the defect is. For example, structural heart defects can be quite complex and sometimes surgery can not fix them. Furthermore, no treatment is available for the mental retardation in the portion of affected individuals with this symptom. Resources PERIODICALS Rugarli, Elena, and Andrea Ballabio. “Kallmann Syndrome: From Genetics to Neurobiology.” JAMA 270, no. 22 (December 8, 1993): 2713–2716. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 629 Kallmann syndrome [...]... of chromosome pairs 6, 7, 8, 9, 10 , 11 and 12 and also includes the X chromosome They are medium-sized and their centromeres either lie in the middle or toward the top of the chromosomes Group D consists of chromosome pairs 13 ,14 and 15 They are medium-sized and their centromeres lie at the top of the chromosomes (acrocentric) Additionally, the D group chromosomes have satellites Group E consists of. .. chromosome pairs 16 , 17 and 18 They are relatively short chromosomes and their centromeres lie in the center or towards the top of the chromosomes Group F consists of chromosomes 19 and 20 They are short chromosomes with centromeres that lie in the center of the chromoGALE ENCYCLOPEDIA OF GENETIC DISORDERS KEY TERMS Acrocentric—A chromosome with the centromere positioned at the top end Centromere The centromere... material at the tips of the short arms of chromosomes 13 , 14 , 15 , 21, and 22 Submetacentric—Positioning of the centromere between the center and the top of the chromosome some Lastly, group G consists of chromosome pairs 21, 22 and the Y chromosome These are short chromosomes with their centromeres at the top Chromosome pairs 21 and 22 have satellites The Y chromosome does not have satellites The actual... the karyotype after the 22nd pair The chromosomes can be separated into groups, based on their length and the position of the centromere Group A consists of chromosome pairs 1, 2 and 3 They are the longest chromosomes and their centromeres are in the center of the chromosomes (metacentric) Group B consists of chromosome pairs 4 and 5 They are long; however, their centromeres lie toward the top of the. .. (flexion) and backwards (extension) occurs in the joints between the base of the skull and the uppermost spinal bone The other half of the motions of flexion and extension occur in the rest of the upper spine Therefore, the danger is due to the excessive motion of the neck between the joints that are fused • Group 2 has fusion of bones (vertebrae) below the second cervical bone (C2) Group 2 also has... expansion of a CAG trinucleotide repeat in the first PART of the gene In unaffected individuals, between 11 to 33 copies OF the CAG trinucleotide are present In patients with Kennedy disease, this number rises to 40 to 62 The greater the number of expanded repeats, the earlier the age of onset Genetic profile Kennedy disease is an X-linked recessive disease, meaning the abnormal gene is found on the X... contractions of the musculature that is visible through the skin) of the tongue, lips or area around the mouth, absence of hyperactive reflexes and spasticity, and often evidence of enlarged breasts and/or small testes with few or no sperm The diagnosis is made by a specific molecular genetic test that measures the number of “repeats” in a particular part of the androgen receptor (AR) gene The alteration of the. .. D.A., et al “Krabbe Disease: Genetic Aspects and Progress Toward Therapy.” Molecular Genetics and Metabolism 70(2000) : 1- 9 ORGANIZATIONS Hunter’s Hope Foundation PO Box 643, Orchard Park, NY 14 127 (877) 984-HOPE Fax: ( 716 ) 667 -1 2 12 Ͻhttp://www.huntershope.orgϾ United Leukodystrophy Foundation 2304 Highland Dr., Sycamore, IL 6 017 8 ( 815 ) 89 5-3 211 or (800) 72 8-5 483 Fax: ( 815 ) 89 5-2 432 Ͻhttp://www ulf.orgϾ... Amaurosis.” Archives of Ophthalmology 11 (February 19 97): 29 3- 294 Perrault, I “Leber Congenital Amaurosis.” Molecular Genetics and Metabolism 68 (October 19 99): 20 0-2 08 ORGANIZATIONS Foundation Fighting Blindness Executive Plaza 1, Suite 800, 11 350 McCormick Rd., Hunt Valley, MD 210 3 1- 1 014 (888) 39 4-3 937 Ͻhttp://www.blindness.orgϾ WEBSITES “Entry 20400: Leber Congenital Amaurosis, Type 1. ” OMIM— Online... sequence There are three classifications of Klippel-Feil sequence • Group 1 exhibits fusion of the lower skull (head) and the first bone of the spine (the first cervical vertebrae (C1)) The second and third spinal bones (cervical vertebrae C2 and C3) are also usually fused together in Group 1 The normal cervical spine has seven bones or vertebrae Normally half of the ability of humans to bend their heads . either lie in the middle or toward the top of the chromosomes. Group D consists of chromosome pairs 13 ,14 and 15 . They are medium-sized and their centromeres lie at the top of the chromosomes. chromosome. Satellites of chromosomes—Small segments of genetic material at the tips of the short arms of chromosomes 13 , 14 , 15 , 21, and 22. Submetacentric—Positioning of the centromere between the center and the. the top of the chromosomes. Group F consists of chromosomes 19 and 20. They are short chromosomes with centromeres that lie in the center of the chromo- GALE ENCYCLOPEDIA OF GENETIC DISORDERS 633 Karyotype KEY

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