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

Resources

BOOKS

Bock, R. Understanding Klinefelter’s Syndrome: A Guide for XXY Males and Their Families. National Institutes of Health, USA, 1993.

Probasco, Teri, and Gretchen A. Gibbs. Klinefelter Syndrome. Richmond, IN: Prinit Press, 1999.

PERIODICALS

Smyth, Cynthia M., and W.J. Bremner. “Klinefelter Syndrome.”

Archives of Internal Medicine 158 (1998): 1309–1314. Smyth, Cynthia M. “Diagnosis and Treatment of Klinefelter

Syndrome.” Hospital Practice (September 15, 1999): 111–120

Staessen, C., et al. “Preimplantation Diagnosis for X and Y Normality in Embryos from Three Klinefelter Patients.” Human Reproduction 11, no. 8. (1996): 1650–1653.

ORGANIZATIONS

American Association for Klinefelter Syndrome Information and Support (AAKSIS) 2945 W. Farwell Ave., Chicago, IL 60645-2925. (773) 761-5298 or (888) 466-5747. Fax: (773) 761-5298. http://www.aaksis.org aaksis@aaksis

.org .

Klinefelter Syndrome and Associates, Inc. PO Box 119, Roseville, CA 95678-0119. (916) 773-2999 or (888) 9999428. Fax: (916) 773-1449. ksinfo@genetic.org.http://www.genetic.org/ks .

Klinefelter’s Organization. PO Box 60, Orpington, BR68ZQ. UK http://hometown.aol.com/KSCUK/index.htm .

WEBSITES

Klinefelter Syndrome Support Group Home Page.http://klinefeltersyndrome.org/index.html .

Carin Lea Beltz, M.S.

I Klippel-Feil sequence

Definition

Individuals with Klippel-Feil sequence (KFS) were originally described as having a classic triad of webbed neck (very short neck), low hairline, and decreased flexibility of the neck. More commonly, abnormal joining or fusion of two or more vertebrae (bones) of the cervical spine (neck bones) characterizes Klippel-Feil sequence.

Description

Klippel-Feil sequence is extensive fusion of multiple cervical vertebrae (the uppermost bones of the spine). There may be complete fusion or multiple irregular bony segments in the bones of the upper back (cervical and often upper thoracic spine). Premature and extensive

arthritis and osseous (bony) spurring affecting the joints of the spine (facet joints) are common in individuals with Klippel-Feil 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 forward (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 an abnormal skull and upper spinal bone connection.

•Group 3 has an open space between two fused segments of spinal bones.

Genetic profile

Although this is usually a sporadic occurrence, an abnormal gene responsible for Klippel-Feil sequence has been found on the q (long) arm of chromosome 8. The human cell contains 46 chromosomes arranged in 23 pairs. Most of the genes in the two chromosomes of each pair are identical or almost identical with each other. However, with KFS individuals, there appears to be a reversal or inversion on part of chromosome 8.

Demographics

Approximately one out of every 42,000 people has Klippel-Feil sequence. The classic triad is seen in 52% of individuals with the syndrome. Men and women are affected equally, however, some studies have shown slightly higher numbers for women. There have been some reports of Klippel-Feil sequence being more common among infants born with fetal alcohol syndrome (FAS) because FAS affects bone development of the fetus. However, there is a genetic component that passes the syndrome on through the generations in a dominant inheritance pattern.

Signs and symptoms

The first clinical signs are the classic triad of webbed neck, low hairline, and decreased flexibility of the neck. However, the presence of abnormalities of the cervical

sequence Feil-Klippel

Klippel-Feil sequence

K E Y T E R M S

Degenerative disc disease—Narrowing of the disc space between the spinal bones (vertebrae).

Fetal alcohol syndrome—Syndrome characterized by distinct facial features and varying mental retardation in an infant due to impaired brain development resulting from the mother’s consumption of alcohol during pregnancy.

Hypoplasia—Incomplete or underdevelopment of a tissue or organ.

Microtia—Small or underdeveloped ears.

Ossicles—Any of the three bones of the middle ear, including the malleus, incus, and stapes.

Radiculopathy—A bulging of disc material often irritating nearby nerve structures resulting in pain and neurologic symptoms. A clinical situation in which the radicular nerves (nerve roots) are inflamed or compressed. This compression by the bulging disc is referred to as a radiculopathy. This problem tends to occur most commonly in the neck (cervical spine) and low back (lumbar spine).

Scoliosis—An abnormal, side-to-side curvature of the spine.

Torticollis—Twisting of the neck to one side that results in abnormal carriage of the head and is usually caused by muscle spasms. Also called wryneck.

spine found with x rays is the hallmark diagnosis. Other signs and symptoms may be found, but vary from person to person.

Some patients may exhibit wryneck or Torticollis, which is a twisting of the neck to one side that results in abnormal carriage of the head. The individual may have differences between the two sides of his face, known as facial asymmetry. They may also have scoliosis (abnormal curves of the spine).

A variety of miscellaneous abnormalities may clinically manifest themselves in Klippel-Feil sequence. Deafness occurs in about 30% of the cases. Ear abnormalities such as very small ear lobes (microtia), or deformed bones within the ear (ossicles) may be present. Patients may even have a small or absent internal ear.

Abnormalities of the blood vessels such as a missing radial artery in the forearm may decrease the size of the thumbs (thenar hypoplasia). Anomalies of the right subclavian artery (artery under the clavicle or collar bone) have been reported as well as higher incidences of artery

anomalies of the upper neck (cervical vertebrae). Anomalies of the genital areas and urinary system are also common.

Individuals diagnosed with Klippel-Feil sequence frequently have problems with cervical nerves and nerves that go from the neck to the arms and hands. Individuals can have pain that starts in their neck and travels into the arms if the nerve roots coming off of the spinal cord are irritated or pinched.

Diagnosis

Klippel-Feil sequence is usually diagnosed in early childhood or adolescence. Observing the clinical signs of having the classic triad of webbed neck, low hairline, and limited cervical ranges of motion initiates the diagnosis. When further testing is done such as x ray, the diagnosis is confirmed by the fusion of multiple cervical vertebrae.

Treatment and management

If the individual has a very mild case of Klippel-Feil sequence, then the person can lead a normal life with only minor restrictions. These restrictions, such as avoiding contact sports that would place the neck at risk, are necessary because of the instability of the cervical spine. This is due to the increased motion between the fused cervical vertebrae.

Symptoms, such as pain, that occur with the arthritis and degeneration of the joints may also result. The individuals should be treated with pain medication and possible cervical traction. If neurological symptoms occur, the treatment of choice is fusion of the symptomatic area. However, due to the severe consequences of not having the preventive surgery, surgery is still the treatment most performed.

Prognosis

There have been reports of death following minor trauma because of injuries to the spinal cord in the cervical spine. Most commonly, individuals with Klippel-Feil will develop pain. Some diseases are acquired or occur because of the increased motion of the vertebrae. Degenerative disc disease, or destruction of the cushion like disc between the vertebrae is very common. The most common findings were degenerative disc disease that affected the entire lower cervical spine. Spondylotic osteophytes, or bone spurs in the spine, form as a result of this degeneration. This laying down of new bone may lead to narrowing of the canal through which the spinal cord travels (spinal stenosis).

Surgery may prevent a dangerous and fatal accident because of the instability of the spinal cord. Pain that

originates in the neck and travels into the arms (radiculopathy) is common near the sites of the surgical fusion of vertebrae. One study found that 25% of the individuals who had surgery would have had neurological problems within ten years, therefore requiring additional surgery.

Resources

BOOKS

Guebert, Gary M., et al. “Congenital Anomalies and Normal Skeletal Variants.” In Essentials of Skeletal Radiology, edited by Terry Yochum and Lindsay Rowe. 2nd ed. Baltimore: Williams & Wilkins, 1996.

Juhl J.H., A.B. Crummy, and J.E. Kuhlman, eds. Paul and

Juhl’s Essentials of Radiologic Imaging. 7th ed. Philadelphia: Lippencot-Raven, 1998.

PERIODICALS

Clarke, Raymond A., et al. “Familial Klippel-Feil Syndrome and Paracentric Inversion inv(8)(q22.2q23.3).” American Journal of Human Genetics 57(1995): 1364–1370.

Clarke, Raymond A, et al. “Heterogenectiy in Klippel-Feil Syndrome: A New Classification.” Pediatric Radiology 28(1998): 967–974.

Hilibrand, A.S., et al. “Radiculopathy and Myelopathy at Segments Adjacent to the Site of a Previous Anterior Cervical Arthrodesis.” Journal of Bone and Joint Surgery

81-A, no. 4 (1999): 519–528.

Nagashima, Hideki. “No Neurological Involvement for More Than 40 Years in Klippel-Feil Syndrome with Hypermobility of the Upper Cervical Spine.” Archives of

Orthopedic Trauma and Surgery 121(2001): 99–101. Thomsen, M.N., et al. “Scoliosis and Congenital Anomalies

Associated with Klippel-Feil Syndrome Types I-Ill.” Spine 22, no. 4 (1997): 396–401.

ORGANIZATIONS

National Institutes of Health (NIH). PO Box 5801, Bethesda, MD 20824. (800) 352-9424. nihinfo@Ood.nih.gov.http://www.ninds.nih.gov/health .

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

KFS Circle of Friends support group. http://www.fortunecity

.com/millenium/bigears/99/kfs.html .

KFS Connection Online, An online Klippel-Feil Support group.http://members.aol.com/kfsconxpgs/links.htm .

Jason S. Schliesser, D.C.

Knobloch syndrome see Encephalocele

Konigsmark syndrome see Hereditary hearing loss and deafness

Kowarski syndrome see Pituitary dwarfism syndrome

I Krabbe disease

Definition

Krabbe disease is an inherited enzyme deficiency that leads to the loss of myelin, the substance that wraps nerve cells and speeds cell communication. Most affected individuals start to show symptoms before six months of age and have progressive loss of mental and motor function. Death occurs at an average age of 13 months. Other less common forms exist with onset in later childhood or adulthood.

Description

Myelin insulates and protects the nerves in the central and peripheral nervous system. It is essential for efficient nerve cell communication (signals) and body functions such as walking, talking, coordination, and thinking. As nerves grow, myelin is constantly being built, broken down, recycled, and rebuilt. Enzymes break down, or metabolize, fats, carbohydrates, and proteins in the body including the components of myelin.

Individuals with Krabbe disease are lacking the enzyme galactosylceramidase (GALC), which metabolizes a myelin fat component called galactosylceramide and its by-product, psychosine. Without GALC, these substances are not metabolized and accumulate in large globoid cells. For this reason, Krabbe disease is also called globoid cell leukodystrophy. Accumulation of galactosylceramide and psychosine is toxic and leads to the loss of myelin-producing cells and myelin itself. This results in impaired nerve function and the gradual loss of developmental skills such as walking and talking.

Genetic profile

Krabbe disease is an autosomal recessive disorder. Affected individuals have two nonfunctional copies of the GALC gene. Parents of an affected child are healthy carriers and therefore have one normal GALC gene and one nonfunctional GALC gene. When both parents are carriers, each child has a 25% chance to inherit Krabbe disease, a 50% chance to be a carrier, and a 25% chance to have two normal GALC genes. The risk is the same for males and females. Brothers and sisters of an affected child with Krabbe disease have a 66% chance of being a carrier.

disease Krabbe

Krabbe disease

K E Y T E R M S

Globoid cells—Large cells containing excess toxic metabolic “waste” of galactosylceramide and psychosine.

Motor function—The ability to produce body movement by complex interaction of the brain, nerves, and muscles.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

The GALC gene is located on chromosome 14. Over 70 mutations (gene alterations) known to cause Krabbe disease have been identified. One specific GALC gene deletion accounts for 45% of disease-causing mutations in those with European ancestry and 35% of diseasecausing mutations in those with Mexican ancestry.

Demographics

Approximately one in every 100,000 infants born in the United States and Europe will develop Krabbe disease. A person with no family history of the condition has a one in 150 chance of being a carrier. Krabbe disease occurs in all countries and ethnic groups but no cases have been reported in the Ashkenazi Jewish population. A Druze community in Northern Israel and two Moslem Arab villages near Jerusalem have an unusually high incidence of Krabbe disease. In these areas, about one person in every six is a carrier.

Signs and symptoms

Ninety percent of individuals with Krabbe disease have the infantile type. These infants usually have normal development in the first few months of life. Before six months of age, they become irritable, stiff, and rigid. They may have trouble eating and may have seizures. Development regresses leading to loss of mental and muscle function. They also lose the ability to see and hear. In the end stages, these children usually cannot move, talk, or eat without a feeding tube.

Ten percent of individuals with Krabbe disease have juvenille or adult type. Children with juvenile type begin having symptoms between three and ten years of age. They gradually lose the ability to walk and think. They may also have paralysis and vision loss. Their symptoms usually progress slower than in the infantile type. Adult Krabbe disease has onset at any time after age 10.

Symptoms are more general including weakness, difficulty walking, vision loss, and diminished mental abilities.

Diagnosis

There are many tests that can be performed on an individual with symptoms of Krabbe disease. The most specific test is done by measuring the level of GALC enzyme activity in blood cells or skin cells. A person with Krabbe disease has GALC activity levels that are zero to five percent of the normal amount. Individuals with later onset Krabbe disease may have more variable GALC activity levels. This testing is done in specialized laboratories that have experience with this disease.

The fluid of the brain and spinal cord (cerebrospinal fluid) can also be tested to measure the amount of protein. This fluid usually contains very little protein but the protein level is elevated in infantile Krabbe disease. Nerve-conduction velocity tests can be performed to measure the speed at which the nerve cells transmit their signals. Individuals with Krabbe disease will have slowed nerve conduction. Brain imaging studies such as computerized tomography (CT scan) and magnetic resonance imaging (MRI) are used to get pictures from inside the brain. These pictures will show loss of myelin in individuals with Krabbe disease.

DNA testing for GALC mutations is not generally used to make a diagnosis in someone with symptoms but it can be performed after diagnosis. If an affected person has identifiable known mutations, other family members can be offered DNA testing to find out if they are carriers. This is helpful since the GALC enzyme test is not always accurate in identifying healthy carriers of Krabbe disease.

If an unborn baby is at risk to inherit Krabbe disease, prenatal diagnosis is available. Fetal tissue can be obtained through chorionic villus sampling (CVS) or amniocentesis. Cells obtained from either procedure can be used to measure GALC enzyme activity levels. If both parents have identified known GALC gene mutations, DNA testing can also be performed on the fetal cells to determine if the fetus inherited one, two, or no GALC gene mutations.

Some centers offer preimplantation diagnosis if both parents have known GALC gene mutations. In-vitro fertilization (IVF) is used to create embryos in the laboratory. DNA testing is performed on one or two cells taken from the early embryo. Only embryos that did not inherit Krabbe disease are implanted into the mother’s womb. This is an option for parents who want a biological child but do not wish to face the possibility of abortion of an affected pregnancy.

Treatment and management

Once a child with infantile Krabbe disease starts to show symptoms, there is little effective treatment. Supportive care can be given to keep the child as comfortable as possible and to counteract the rigid muscle tone. Medications can be given to control seizures. When a child can no longer eat normally, feeding tubes can be placed to provide nourishment.

Affected children who are diagnosed before developing symptoms (such as through prenatal diagnosis) can undergo bone marrow transplant or stem cell transplant. The goal of these procedures is to destroy the bone marrow which produces the blood and immune system cells. After the destruction of the bone marrow, cells from a healthy donor are injected. If successful, the healthy cells travel to the bone marrow and reproduce. Some children have received these transplants and had a slowing of their symptom’s progression or even improvement of their symptoms. However, these procedures are not always successful and research is being done in order to reduce complications.

Scientists are also researching gene therapy for Krabbe disease. This involves introducing a normal GALC gene into the cells of the affected child. The goal is for the cells to integrate the new GALC gene into its DNA and copy it, producing functional GALC enzyme. This is still in research stages and is not being performed clinically.

Prognosis

Prognosis for infantile and juvenile Krabbe disease is very poor. Individuals with infantile type usually die at an average age of 13 months. Death usually occurs within a year after the child shows symptoms and is diagnosed. Children with juvenile type may survive longer after diagnosis but death usually occurs within a few years. Adult Krabbe disease is more variable and difficult to predict but death usually occurs two to seven years after diagnosis.

Resources

BOOKS

Wenger, 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 14127. (877) 984-HOPE. Fax: (716) 667-1212.http://www.huntershope.org .

United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. http://www. ulf.org .

WEBSITES

Wenger, David A. “Krabbe Disease.” GeneClinics. http://www

.geneclinics.org/profiles/krabbe/details.html .

Amie Stanley, MS

disease Krabbe

Lamellar ichthyosis see Ichthyosis

I Langer-Giedion syndrome

Definition

Langer-Giedion syndrome (LGS) is a rare genetic disorder characterized by skeletal abnormalities and dysmorphic (distinctive) facial features. Most people with LGS also have mental retardation.

Description

LGS affects mostly the skeletal system and facial structure. Since the features include abnormalities in the hair (tricho), nose shape (rhino), and fingers and toes (phalangeal), another name for LGS is tricho-rhino-pha- langeal syndrome, type II.

Genetic profile

LGS is not usually passed through generations in a family. However, the condition is considered a contigu- ous-gene syndrome. This means that it is caused by the loss of functional copies of two genes near each other on chromosome 8. Research suggests that another gene may be involved. Genetic counseling is suggested for anyone considering pregnancy who has a relative with this condition.

Demographics

About 50 cases of Langer-Giedion syndrome have been reported in the literature. Males are affected three times more often than females.

Signs and symptoms

Craniofacial features associated with LangerGiedion syndrome include a bulbous, pear-shaped nose;

a small jaw; a thin upper lip; and large ears. The hair is usually sparse, and the head is small in 60% of individuals with LGS. Mild to severe mental retardation is present in 70% of people; it often affects speech more than other skills.

Skeletal features include exostoses—spiny growths on the bone—which occur before age five and usually increase in number until the skeleton matures. Compression of nerves or blood vessels, asymmetric limb growth, and limitation of movement are problems that can result from the exostoses. Scoliosis—a curvature of the spine—is found in some people, as well as thin ribs. Short stature is often seen as a result of epiphyses— cone-shaped bone ends. Longitudinal bone growth appears to be slowed. Short and/or curved fingers are common. Loose skin often occurs, but that tends to improve with age.

Features of LGS that are less commonly seen include loose joints and low muscle tone. Others are wandering eye (exotropia), droopy eyelid, widely spaced eyes, fractures in the bones, birthmarks that increase with age, hearing loss, heart or genito-urinary abnormalities, and webbing of the fingers.

Diagnosis

The criteria for diagnosis of LGS are a bulbous, pear-shaped nose, and epiphyses and exostoses. These signs are probably all related to abnormal bone growth, but researchers do not yet understand the link to mental retardation and hair abnormalities. The distinctive facial features may be recognized at birth. Changes in the epiphyses are recognizable through x ray by age three, and exostoses are visible by age five. Chromosome analysis will likely reveal an abnormality in a certain region of chromosome 8.

There are no reports of prenatal diagnosis of this condition. To provide accurate genetic counseling regarding prognosis and risk of recurrence, it is important to distinguish this condition from others that are similar to it, such as tricho-rhino-phalangeal syndrome, type 1.

Larsen syndrome

K E Y T E R M S

Contiguous gene syndrome—A genetic syndrome caused by the deletion of two or more genes located next to each other.

Craniofacial—Relating to or involving both the head and the face.

Epiphysis—The end of long bones, usually terminating in a joint.

Exostose—An abnormal growth (benign tumor) on a bone.

Mental retardation—Significant impairment in intellectual function and adaptation in society. Usually associated with an intelligence quotient (IQ) below 70.

Philtrum—The center part of the face between the nose and lips that is usually depressed.

Short stature—Shorter than normal height, can include dwarfism.

Treatment and management

The treatment for LGS is tailored to each person. Exostoses may need to be surgically removed if they are causing problems with nerves or blood vessels. If the two leg lengths are different, corrective shoes may be helpful. Orthopedic devices such as braces or, more rarely, surgery may be indicated in severe cases of skeletal abnormality. Plastic surgery to alter specific features, such as the ears or nose, has been chosen by some people.

The risk of cancer at the site of the exostoses is not known but may be higher.

Special education for mentally retarded individuals is indicated. A focus on speech development may be appropriate.

Prognosis

Langer-Giedion syndrome does not alter lifespan. Complications from associated abnormalities such as mental retardation, however, can cause problems. Asymmetry of the limbs can interfere with their function and cause pain. Psychological effects due to physical abnormalities may also be experienced.

Resources

BOOKS

“Tricho-rhino-phalangeal Syndrome, Type II.” In Birth Defects

Encyclopedia, ed. Mary Louise Buyse. Boston: Blackwell

Scientific Publications, 1990.

Goodman, Richard M., and Robert J. Gorlin. “Langer-Giedion Syndrome.” In The Malformed Infant and Child, by New York: Oxford University Press, 1983.

PERIODICALS

Moroika, D., and Y. Hosaka. “Aesthetic and Plastic Surgery for Trichorhinophalangeal Syndrome.” Aesthetic Plastic Surgery 24 (2000): 39-45.

ORGANIZATIONS

Langer-Giedion Syndrome Association. 89 Ingham Ave., Toronto, Ontario M4K 2W8, Canada. (416) 465-3029. kinross@istar.ca.

National Institute on Deafness and Other Communication Disorders. 31 Center Dr., MSC 2320, Bethesda, MD 20814. (301) 402-0900. nidcdinfo@nidcd.nih.gov.http://www.nidcd.nih.gov .

WEBSITES

NORD—National Organization for Rare Diseases.

http://www.rarediseases.org .

OMIM—Online Mendelian Inheritance in Man.

http://www.ncbi.nlm.nig.gov .

Amy Vance, MS, CGC

Langer-Saldino syndrome see

Achondrogenesis

I Larsen syndrome

Definition

Larsen syndrome is an inherited condition characterized by congenital dislocation of multiple body joints along with other unusual features of the face, hands, and bones.

Description

This condition was first described in 1950 by Larsen, Schottstaedt, and Bost, who compiled information on six people with sporadic cases of Larsen syndrome.

Larsen syndrome has been called both a skeletal dysplasia (a condition caused by abnormalities of bone structure), and a hypermobility syndrome (a condition involving abnormally loose joints). It is most likely caused by inherited abnormalities of connective tissue that affect both bone and joint structure.

Present at birth are multiple dislocations of the elbows, hips, and most commonly the knees. Persons with Larsen syndrome have other distinctive physical features that can include a prominent forehead, widely spaced eyes, long cylindrical fingers, and short bones of

the hand. Sometimes present are other birth defects such as structural heart defects, cleft palate, cataracts, extra bones of the wrist, and abnormalities of the vertebrae.

Most people have moderate symptoms that can be treated, allowing for a relatively normal life span. However, a small number of babies have a severe form of the condition and die at birth.

Genetic profile

There are likely to be multiple different causes for Larsen syndrome. Both recessive and dominant patterns of inheritance have been described thus far.

Some cases are sporadic, meaning the affected person is the first in the family to have the condition. Many sporadic cases are though to be cause by new dominant mutations (spontaneous changes in the genetic material). A person with sporadic Larsen syndrome has a change in the genetic material that is not present in either parent but can be passed on, with 50/50 odds in each child, to his or her offspring.

Patients have been reported who have affected brothers or sisters but unaffected parents. Most of these cases probably represent a recessive form of Larsen syndrome in which a person must have two copies of a genetic change in order to be affected. The parents of a person with a recessive condition must each have one copy of the genetic change in order to have an affected child.

There are rare instances in which a person with Larsen appears to have the recessive form but then gives birth to an affected child. These cases are most likely dominant rather than recessive. It can be difficult to be certain of the inheritance pattern in some families and genetic counselors must be careful to address both forms of inheritance when discussing chances of recurrence.

The autosomal dominant form of Larsen syndrome is thought to be due to mutations in a gene called LAR1, on the short arm of chromosome 3. The exact structure and function of this gene is not yet known. There may be other genes responsible for a proportion of cases of dominant Larsen syndrome; however, as of 2001, no other candidate genes have been located.

Another dominantly inherited condition called Atelosteogenesis Type III (AOIII) has features which overlap with Larsen syndrome, and may, in fact, be a variant of Larsen caused by mutations in the same gene.

Demographics

Larsen syndrome is an extremely rare genetic condition that occurs in about one in every 100,000 births.

A variant of Larsen syndrome is found in high frequency on La Reunion island near East Africa. Over 40

K E Y T E R M S

Arthrogryposis—Abnormal joint contracture. Carrier—A person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring.

Clubfoot—Abnormal permanent bending of the ankle and foot. Also called talipes equinovarus. Congenital—Refers to a disorder that is present at birth.

Connective tissue—A group of tissues responsible for support throughout the body; includes cartilage, bone, fat, tissue underlying skin, and tissues that support organs, blood vessels, and nerves throughout the body.

Contrature—A tightening of muscles that prevents normal movement of the associated limb or other body part.

Deformation—An abnormal form or position of a part of the body caused by extrinsic pressure or mechanical forces.

Epiphysis—The end of long bones, usually terminating in a joint.

Hypermobility—Unusual flexibility of the joints, allowing them to be bent or moved beyond their normal range of motion.

Joint dislocation—The displacement of a bone from its socket or normal position.

Kyphosis—An abnormal outward curvature of the spine, with a hump at the upper back.

Magnetic resonance imaging (MRI)—A technique that employs magnetic fields and radio waves to create detailed images of internal body structures and organs, including the brain.

Scoliosis—An abnormal, side-to-side curvature of the spine.

Skeletal dysplasia—A group of syndromes consisting of abnormal prenatal bone development and growth.

affected children have been reported, with an incidence of 1/1500 births. This variant is thought to be recessive but the responsible gene has not yet been located.

Signs and symptoms

The symptoms of Larsen syndrome are widely variable from person to person and can range from lethal to very mild, even among members of the same family.

syndrome Larsen

Larsen syndrome

Typical characteristics at birth are multiple joint dislocations that can include hips, elbows, wrists, and knees. Babies can be born with their knees in hyperextension with their ankles and feet up by their ears, a deformation called genu recurvatum. Clubfoot is common and persistent flexion, or contractures, of other joints, such as the wrist and fingers, can also occur.

Persons with Larsen syndrome often have distinctive facial features. Common findings, in addition to a large forehead and wide spaced eyes, are flat cheekbones and a flat bridge of the nose, which is sometimes indented and called “saddle nose”. The hands are often short but the fingers are long and lack the normal tapered ends.

Other birth defects can occur but are not present in all people. Cleft palate, cataracts, and heart defects of the valves or between the upper or lower chambers occur occasionally.

Often, babies have floppy muscle tone giving them a “rag doll” appearance. Respiratory problems are frequently seen at birth because of laxity of the trachea. Feeding and swallowing difficulties are common.

Abnormalities of the bones are frequent. Underdevelopment and abnormal shape of some of the vertebral bones can lead to problems such as scoliosis or kyphosis. Abnormalities of the epiphyses (centers of bone growth) can develop in childhood. Height is often reduced, and an adult height of four to five feet is not uncommon. The joints between the bones of the ear may be abnormal and may cause conductive hearing loss.

Hypermobility of joints lasts throughout life and may lead to early-onset arthritis, recurrent dislocations, and may necessitate joint replacement at an early age. Cervical spine instability is a very serious complication of Larsen syndrome as it can cause compression of the spinal cord and lead to paralysis or death.

The condition does not affect intelligence and children can expect to have normal school experiences, with the exception of physical education, which will need to be adapted to each child’s needs.

Diagnosis

Larsen syndrome should be suspected in any baby having multiple joint dislocations at birth. As of 2001, there is no genetic test to confirm the diagnosis and, thus, diagnosis must be based on clinical and x ray findings. Babies suspected to have the condition warrant a complete evaluation by a medical geneticist (a physician specializing in genetic syndromes).

Larsen syndrome is sometimes misdiagnosed as another condition called arthrogryposis, which involves multiple joint contractions. Larsen syndrome can be dis-

tinguished from this and other syndromes involving joint dislocations or contractions because of the unusual constellation of features found in the face and hands. Extra bones of the wrist, often seen in Larsen syndrome, are extremely rare in other syndromes.

Some people have very mild symptoms and may not have joint dislocations or other problems at birth. The diagnosis can be missed in these people unless they are carefully evaluated.

A person with dominantly inherited Larsen syndrome has a 50% chance with each pregnancy of having a child with the same disorder. Genetic counseling can help couples sort out their options for parenthood. Some couples would choose to adopt rather than take the chance of an affected child, others would go ahead with a pregnancy, and others would choose to have prenatal diagnosis. The only form of prenatal diagnosis available to date is ultrasound.

Fetal ultrasound performed by a specialist at 18-20 weeks of pregnancy can sometimes reveal signs of Larsen syndrome. Knee dislocations and hyperextension, club feet, fixed flexion of elbows, wrists, and fingers, and some of the characteristic facial features can sometimes be noted by ultrasound in affected fetuses. Physical findings from ultrasound can suggest but do not confirm the diagnosis of Larsen syndrome in a fetus.

Treatment and management

Treatment will vary according to the symptoms of a particular child. Joint problems require long-term orthopedic care. Dislocations, clubfeet, and joint contractures are treated with intensive physical therapy, splints, casting, and/or surgery. Physical therapy is also important after joint surgery to build up muscles around the joint and preserve joint stability. Occupational therapy may be helpful for children with wrist and finger contractures.

Respiratory problems at birth may necessitate oxygen or assistive breathing devices. If not alleviated by medication or special feeding techniques, eating and swallowing problems may require tube feeding. Heart problems, cleft palate, and cataracts often warrant surgical correction. Special care is needed if laxity of the trachea is present because of an increased risk for respiratory problems during and after surgery.

People with chronic pain associated with hypermobile joints often can be helped by techniques taught in a pain management clinic.

Magnetic resonance imaging (MRI) of the neck is recommended in childhood to screen for cervical vertebral problems. Early diagnosis and surgical stabilization of the spine can help patients avoid paralysis and death

from spinal cord compression. Scoliosis is usually treated by bracing, or by a surgically placed metal rod. Artificial hip and knee replacements may be needed in early-to- mid adulthood because of degeneration of unstable joints.

Regular medical examinations are crucial to assess the condition of the bones, joints, spine, heart, and eyes. Hearing should be evaluated on a periodic basis, especially in children, because of the potential for conductive hearing loss. Ophthalmologic examinations are recommended periodically to screen for cataracts.

Prognosis

The effects of the syndrome vary markedly from person to person. Therefore, prognosis is based on the findings in a given individual. The usual causes of early death are either severe respiratory problems or compression of the cervical spine from vertebral instability.

If careful and consistent orthopedic treatment is initiated early, prognosis can be good, with a normal life span. Weak and unstable joints and limited range of motion from contractures may cause walking difficulties and restrict other physical activities. Contact sports and heavy lifting should be avoided as anything that puts extra strain or pressure on the joints can cause harm. Swimming is a good activity because it helps strengthen muscles without joint strain.

Resources

PERIODICALS

Becker, R., et al. “Clinical Variability of Larsen Syndrome: Diagnosis in a Father after Sonographic Detection of a Severely Affected Fetus.” Clinical Genetics 57 (2000): 148-150.

Tongsong, T., et al. “Prenatal Sonographic Diagnosis of Larsen Syndrome.” Journal of Ultrasound Medicine 19 (2000): 419-421.

ORGANIZATIONS

Arthritis Foundation. 1330 West Peachtree St., Atlanta, GA

30309. (800) 283-7800 or (404)965-7537. http://www

.arthritis.org .

Scoliosis Research Society. 6300 N. River Rd., Ste 727,

Rosemont, IL 60018-4226. (847)698-1627. Fax: (847)

823-0536. Goulding@aaos.org. http://www.srs.org/ .

WEBSITES

Larsen Syndrome Resource Page.http://www.stormloader.com/nita/ls.html

Hypermobility Syndrome Association.http://www.hypermobility.org/

Barbara J. Pettersen

Late onset multiple carboxylase deficiency see Biotinidase deficiency

Laurence-Moon-Bardet-Biedel syndrome see Bardet-Biedel syndrome

I Leber congenital amaurosis

Definition

Leber congenital amaurosis (LCA) is a group of autosomal recessive-inherited eye disorders which lead to blindness at birth or within the first few years of life. Other manifestations of the disease may include hearing loss, mental retardation, and decreased physical coordination.

Description

Vision is an important and complex sense by which the qualities of an object, such as color, shape, and size, are perceived through the detection of light. For proper vision, a critical series of biological steps must occur; if any of the steps in the process is abnormal, visual impairment or blindness may occur.

The process of vision begins with light that bounces off an object and passes through the outer coverings and lens of the eye and projects onto a layer of cells at the back of the eye called the retina. The retina contains two kinds of specialized cells types, called the rods and cones, that are responsible for sensing visual stimuli. When rods and cones are stimulated by light, impulses are conducted through the optic nerve to a region in the back of the brain known as the occipital lobe. The occipital lobe contains the visual cortex, the area of the brain that processes visual stimuli and integrates signals sent by the retina to obtain a composite image of an object.

Leber congenital amaurosis (LCA) is term for a group of inherited conditions in which the rod and cone receptors in the retina are defective or missing. Without the proper function of these specialized cells, light cannot be sensed normally.

LCA is often referred to by other names, such as: congenital absence of the rods and cones, congenital retinal blindness, congenital retinitis pigmentosa, Leber’s congenital tapetoretinal degeneration, or Leber’s congenital tapetoretinal dysplasia. The disorder was first described by the German ophthalmologist, Theodor Leber, in 1869, who subsequently showed that it was an inherited defect. Although similarly named, LCA should

amaurosis congenital Leber