Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

Jervell and Lange-Nielsen syndrome

Prognosis

Approximately 25% of affected children die before two years of age mainly from cardiac defects, a tendency to bleed, or infection. Except for respiratory infections, the remainder of children are generally healthy. Most individuals described here are children or adolescents. Little is known about the course of this syndrome in adulthood, and the life expectancy for those who live beyond age two is unknown.

Resources

BOOKS

Jones, Kenneth Lyons. Smith’s Recognizable Patterns of Human

Malformation. Philadelphia: W.B. Saunders Company, 1997.

PERIODICALS

Jones, Christopher, et al. “Co-localisation of CCG repeats and chromosome deletion breakpoints in Jacobsen syndrome: evidence for a common mechanism of chromosome breakage.” Human Molecular Genetics 9, no. 8: 1201–08.

McClelland, S.M., et al. “Nuchal thickening in Jacobsen syndrome.” Ultrasound in Obstetrics and Gynecology 12 (1998): 280–82.

Ono, J., et al. “Partial deletion of the long arm of chromosome 11: ten Japanese children.” Clinical Genetics 50 (1996): 474–78.

Penny, Laura A., et al. “Clinical and Molecular Characterization of Patients with Distal 11q Deletions.” American Journal of Human Genetics 56 (1995): 676–83.

Pivnick, E. K., et al. “Jacobsen syndrome: report of a patient with severe eye anomalies, growth hormone deficiency, and hypothyroidism associated with deletion 11(q23q25) and review of 52 cases.” Journal of Medical Genetics 33 (1996): 772–78.

Tunnacliffe, Alan, et al. “Localization of Jacobsen syndrome breakpoints on a 40-Mb physical map of distal chromosome 11q.” Genome Research 9 (1999): 44–52.

ORGANIZATIONS

European Chromosome 11q Network. http://www.11q.org .

OTHER

11q Research and Resource Home Page.

http://www.11q.net .

The Fragile WEB Site. http://web.ukonline.co.uk .

Dawn Cardeiro, MS, CGC

I Jervell and

Lange-Nielsen syndrome

Definition

Jervell and Lange-Nielsen syndrome (JLNS) is a rare inherited disorder characterized by congenital deaf-

ness and cardiac arrhythmias (irregularities in the electrical activity of the heart that can lead to cardiac arrest and sudden death).

Description

JLNS results from mutations, or changes, in either one of two genes that encode proteins that combine to form potassium ion channels. One of the potassium channels is important for proper heart function. It is also critical in the functioning of the cochlea of the inner ear. People with JLNS lack this channel and, thus, are born with profound deafness in both ears, as well as with cardiac abnormalities.

JLNS was first described in 1957 by A. Jervell and F. Lange-Nielsen. It is also known by the names cardioauditory syndrome of Jervell and Lange-Nielsen; cardocardiac syndrome; surdocardiac syndrome; deafness-functional heart disease; and deafness, congenital, and functional heart disease. The cardiac (heart) symptoms of JLNS are very similar to those of long-QT syndrome (LQTS), including a longer-than-normal “QT interval” on an electrocardiogram (ECG or EKG) test. Thus, JLNS is sometimes called QT prolonged with congenital deafness.

Genetic profile

JLNS is caused by mutations in either the KVLQT1 (KCNQ1) gene or the KCNE1 (MinK or IsK) gene. It is an autosomal recessive disorder, which means it occurs only in people with two copies of the mutant gene, one from each parent. The mutations in the two copies do not have to be identical. Someone who inherits one copy of the mutant gene and one copy of the normal gene has LQTS types 1 or 5.

Demographics

Although it is the third most common type of autosomal recessive hearing loss, JLNS is a very rare disorder. Worldwide, there are an estimated two to six cases per one million people. Norway, however, has a much higher incidence of JLNS, estimated at one in 200,000.

Because JLNS requires two copies of the abnormal gene, one from each parent, it most often is found in the offspring of related parents, such as cousins (termed a “consanguineous” marriage). Individuals who carry one copy of the abnormal gene and one normal gene copy will have LQTS, but will have normal hearing or only partial hearing loss. However, a child of two such individuals has a 25% chance of having JLNS. Thus, although JLNS occurs across racial and ethnic groups, it is more common in small isolated groups where marriage between relatives is frequent.

syndrome Nielsen-Lange and Jervell

Joubert syndrome

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 correct 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 LangeNielsen 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. http://www.americanheart.org .

American Society for Deaf Children. PO Box 3355, Gettysburg, PA 17325. (800) 942-ASDC or (717) 334-

7922 v/tty. http://www.deafchildren.org/asdc2k/home/ home.shtml .

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. http://www.theearfound

.org .

European Long QT Syndrome Information Center. Ronnerweg 2, Nidau, 2560. Switzerland 04(132) 331-5835. jmettler@bielnews.ch. http://www.bielnews.ch/cyberhouse/ qt/qt.html .

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. http://www

.sads.org .

WEBSITES

Contie, Victoria L. “Genetic Findings Help Tame the Runaway Heart.” NCAA Reporter. http://www.ncrr.nih.gov/ newspub/ nov97rpt/heart.htm (November-December 1997).

“Genetics of Long QT Syndrome/Cardiac Arrest.” DNA Sciences.http://my.webmd.com/content/article/3204.676 (2001).

Long QT Syndrome European Information Center. http:// www.qtsyndrome.ch/lqts.html

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). http://archpedi.ama-assn.org/ issues/ v153n4/ffull/ppm8451-1b.html (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

(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 correctly. 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,

K E Y T E R M S

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 narrow 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 facilitate 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 pigment 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 alternates between deep rapid breathing (almost like panting) with periods of severe apnea (loss of breathing). This is usually noticeable at birth. The rate of respira-

syndrome Joubert

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.)

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 learning 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 eyebrows 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

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.http://www.geneticalliance.org.htm .

Joubert Syndrome Foundation Corporation.http://www.joubertfoundation.com .

Kevin M. Sweet, MS, CGC

syndrome Joubert

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 population 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

Kabuki syndrome

K E Y T E R M S

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.

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 antiseizure medications is often necessary.

Children with Kabuki syndrome often have difficulties 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 regularly 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

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 intestinal 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. http://www

.ksn-support.org.uk .

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 .

WEBSITES

“Entry 147920: Kabuki Syndrome.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/ entrez/dispomim.cgi?id 147920 .

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 dysplasia 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-chro- mosomes (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.

syndrome Kallmann

Kallmann syndrome

K E Y T E R M S

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 controls heartbeat, body temperature, thirst, hunger, body temperature and pressure, blood sugar levels, and other functions.

Neuron—The fundamental nerve cell that conducts 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 folliclestimulating 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-

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 production 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.