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

Lesch-Nyhan syndrome

MAGIC Foundation for Children’s Growth. 1327 N. Harlem Ave., Oak Park, IL 60302. (708) 383-0808 or (800) 3624423. Fax: (708) 383-0899. mary@magicfoundation.org.http://www.magicfoundation.org/ghd.html .

WEBSITES

“Entry 312865: Short Stature Homeo Box; SHOX.” OMIM— Online Mendelian Inheritance of Man. http://www.ncbi

.nlm.nih.gov:80/entrez/dispomim.cgi?id 312865 . Family Village. http://www.familyvillage.wisc.edu/index

.html

Dawn A. Jacob, MS

I Lesch-Nyhan syndrome

Definition

Lesch-Nyhan syndrome is a rare genetic disorder that affects males. Males with this syndrome develop physical handicaps, mental retardation, and kidney problems. It is caused by a total absence of an enzyme. Self injury is a classic feature of this genetic disease.

Description

Lesch-Nyhan syndrome was first described in 1964 by Dr. Michael Lesch and Dr. William Nyhan. The syndrome is caused by a severe change (mutation) in the HPRT gene. This gene is responsible for the production of the enzyme called hypoxanthine-guanine phosphoribosyltransferase (HPRT). HPRT catalyzes a reaction that is necessary to prevent the buildup of uric acid. A severe mutation in the HPRT gene leads to an absence of HPRT enzyme activity which, in turn, leads to markedly elevated uric acid levels in the blood (hyperuricemia). This buildup of uric acid is toxic to the body and is related to the symptoms associated with the disease. Absence of the HPRT enzyme activity is also thought to alter the chemistry of certain parts of the brain, such as the basal ganglia, affecting neurotransmitters (chemicals used for communication between nerve cells), acids, and other chemicals. This change in the nervous system is also related to the symptoms associated with Lesch-Nyhan syndrome.

Males with Lesch-Nyhan syndrome develop neurologic problems during infancy. Infants with Lesch-Nyhan syndrome have weak muscle tone (hypotonia) and are unable to develop normally. Affected males develop uncontrollable writhing movements (athetosis) and muscle stiffness (spasticity) over time. Lack of speech is also a common feature of Lesch-Nyhan syndrome. The most dramatic symptom of Lesch-Nyhan syndrome is the

K E Y T E R M S

Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Athetosis—A condition marked by slow, writhing, involuntary muscle movements.

Basal ganglia—A section of the brain responsible for smooth muscle movement.

Chorea—Involuntary, rapid, jerky movements.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother’s vagina or abdominal wall and a sample of cells is collected from around the fetus. These cells are then tested for chromosome abnormalities or other genetic diseases.

Enzyme—A protein that catalyzes a biochemical reaction or change without changing its own structure or function.

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.

Neurotransmitter—Chemical in the brain that transmits information from one nerve cell to another.

Palsy—Uncontrollable tremors.

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

compulsive self-injury seen in 85% of affected males. This self injury involves the biting of their own lips, tongue, and finger tips, as well as head banging. This behavior leads to serious injury and scarring.

Genetic profile

Severe changes (mutations) in the HPRT gene completely halt the activity of the enzyme HPRT. There have been many different severe mutations identified in the HPRT gene. These mutations may be different within

families. Since the HPRT gene is located on the X chromosome, Lesch-Nyhan syndrome is considered an X- linked disorder. This means that it only affects males.

A person’s sex is determined by their chromosomes. Males have one X chromosome and one Y chromosome. Females, on the other hand, have two X chromosomes. Males who possess a severe mutation in their HPRT gene will develop Lesch-Nyhan syndrome. Females who possess a severe mutation in their HPRT gene will not; they are considered carriers. This is because females have another X chromosome without the mutation that prevents them from getting this disease. If a woman is a carrier, she has a 50% risk with each pregnancy to pass on her X chromosome with the mutation. Therefore, with every male pregnancy she has a 50% risk to have an affected son, and with every female pregnancy she has a 50% risk to have a daughter who is a carrier.

Demographics

Lesch-Nyhan syndrome affects approximately one in 380,000 live births. It occurs evenly among races. Almost always, only male children are affected. Women carriers usually do not have any symptoms. Women carriers can occasionally develop inflammation of the joints (gout)as they get older.

Signs and symptoms

At birth, males with Lesch-Nyhan syndrome appear completely normal. Development is usually normal for the first few months. Symptoms develop between three to six months of age. Sand-like crystals of uric acid in the diapers may be one of the first symptoms of the disease. The baby may be unusually irritable. Typically, the first sign of nervous system impairment is the inability

to lift their head or sit up at an appropriate age. Many patients with Lesch-Nyhan will never learn to walk. By the end of the first year, writhing motions (athetosis), and spasmodic movements of the limbs and facial muscles (chorea) are clear evidence of defective motor development.

The compulsive self-injury associated with LeschNyhan syndrome begins, on average, at three years. The self-injury begins with biting of the lips and tongue. As the disease progresses, affected individuals frequently develop finger biting and head banging. The self-injury can increase during times of stress.

Males with Lesch-Nyhan disease may also develop kidney damage due to kidney stones. Swollen and tender joints (gout) is another common problem.

Diagnosis

The diagnosis of Lesch-Nyhan syndrome is based initially on the distinctive pattern of symptoms. Measuring the amount of uric acid in a person’s blood or urine can not definitively diagnose Lesch-Nyhan syndrome. It is diagnosed by measuring the activity of the HPRT enzyme through a blood test. When the activity of the enzyme is very low it is diagnostic of Lesch-Nyhan syndrome. It can also be diagnosed by DNA testing. This is also a blood test. DNA testing checks for changes (mutations) in the HPRT gene. Results from DNA testing are helpful in making the diagnosis and also if the family is interested in prenatal testing for future pregnancies.

Prenatal diagnosis is possible by DNA testing of fetal tissue drawn by amniocentesis or chorionic villus sampling (CVS). Fetuses should be tested if the mother is a carrier of a change (mutation) in her HPRT gene. A woman is at risk of being a carrier if she has a son with Lesch-Nyhan syndrome or someone in her family has

Leukodystrophy

Lesch-Nyhan syndrome. Any woman at risk of being a carrier should have DNA testing through a blood test.

Treatment and management

There are no known treatments for the neurological defects of Lesch-Nyhan. The medication Allopurinol can lower blood uric acid levels. This medication does not correct many of the symptoms. Some patients with Lesch-Nyhan syndrome have their teeth removed to prevent self-injury. Restraints are recommended to reduce self-destructive behaviors.

Prognosis

With strong supportive care, infants born with Lesch-Nyhan can live into adulthood with symptoms continuing throughout life.

At present, there are no preventive measures for Lesch-Nyhan syndrome. However, recent studies have indicated that this genetic disorder may be a good candidate for treatment with gene replacement therapy. Unfortunately, the technology necessary to implement this therapy has not yet been perfected.

Resources

BOOKS

Jinnah, H.A., and Theodore Friedmann. “Lesch-Nyhan Disease and Its Variants.” The Metabolic and Molecular Bases of

Inherited Disease. New York: McGraw-Hill, 2001.

PERIODICALS

Lesch, M., and W.L. Nyhan. “A Familial Disorder of Uric Acid Metabolism and Central Nervous System Function.”

American Journal of Medicine 36 (1964): 561–570.

Mak, B.S., et al. “New Mutations of the HPRT Gene in LeschNyhan Syndrome.” Pediatric Neurology (October 2000): 332–335.

Visser, J.E., et al. “Lesch-Nyhan Disease and the Basal Ganglia.” Brain Research Reviews (November 1999): 450–469.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. http://www.geneticalliance.org .

International Lesch-Nyhan Disease Association. 114 Winchester Way, Shamong, NJ 08088-9398. (215) 6774206.

Lesch-Nyhan Syndrome Registry. New York University School of Medicine, Department of Psychiatry, 550 First Ave., New York, NY 10012. (212) 263-6458.

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

GeneClinicshttp://www.geneclinics.org/profiles/lns/details.html .

Pediatric Database(PEDBASE) http://www.icondata.com/ health/pedbase/files/LESCH-NY.HTM .

Holly Ann Ishmael, MS, CGC

I Leukodystrophy

Definition

Leukodystrophy describes a collection of about 15 rare genetic disorders that effect the brain, spinal cord and peripheral nerves. It is characterized by imperfect growth or development of the white matter covering nerve fibers in the brain.

Description

Leukodystrophy comes from the Greek words leuko meaning white (referring to the white matter of the nervous system) and dystrophy meaning imperfect growth or development. The white matter is called the myelin sheath and is an extremely complex substance composed of at least 10, and probably more, chemicals. The myelin sheath protects the axon (a long and single-nerve cell process that acts as a wire to conduct impulses away from the cell body), much the way insulation does to an electric wire.

Each type of leukodystrophy affects one of these chemicals. Leukodystrophies covered in this essay are Alexander’s disease, childhood ataxia with central nervous system hypomyelination (CACH), also known as vanishing white matter disease, cerebralautosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy, ovarioleukodystrophy syndrome, and Van der Knapp syndrome, also called vacuolating leukodystrophy with subcortical cysts.

Leukodystrophies covered as separate entries in this encyclopedia are adrenoleukodystrophy (ALD)/adrenomyeloneuropathy (AMN), Aicardi-Goutieres syndrome, canavan disease (spongy degeneration), Krabbe disease (globoid cell leukodystrophy), neonatal adrenoleukodystrophy, Pelizaeus-Merzbacher disease (X-linked spastic paraplegia), Refsum disease, and Zellweger syndrome.

Genetic profile

Genes are the blueprint for the human body that directs the development of cells and tissue. Mutations in

some genes can cause genetic disorders such as leukodystrophy. Every cell in the body has 23 pairs of chromosomes, 22 pairs of which are called autosomes and contain two copies of individual genes. The 23rd pair of chromosomes is called the sex chromosome because it determines a person’s sex. Males have an X and a Y chromosome while females have two X chromosomes.

All of the leukodystrophies discussed in this article have an autosomal recessive pattern of inheritance that affects males and females. People with only one abnormal gene are carriers but since the gene is recessive, they do not have the disorder. Their children will be carriers of the disorder but not show symptoms of the disease. Both parents must have one of the abnormal genes for a child to have symptoms of an autosomal recessive leukodystrophy. When both parents have the abnormal gene, there is a 25% chance each child will inherit both abnormal genes and have the disease. There is a 50% chance each child will inherit one abnormal gene and become a carrier of the disorder but not have the disease itself. There is a 25% chance each child will inherit neither abnormal gene and not have the disease nor be a carrier.

Demographics

All of the leukodystrophies discussed here appear to affect all racial and ethnic groups and all geographic populations. However, metachromatic leukodystrophy has been found in a higher frequency in highly inbred groups, such as the Habbanite Jewish population. Van der Knapp syndrome has a high prevalence among Turkish and Asian-Indian people.

Signs and symptoms

The most common signs seen in most leukodystrophies include gradual changes in an infant or child who previously appeared healthy. These changes may appear in body tone, movements, gait, speech, the ability to eat, hearing, vision, behavior, and memory. Specific signs and symptoms for individual leukodystrophies include:

•Metachromatic, with the most common and most severe form occurring between the ages of six months and two years with symptoms such as irritability, decreased muscle tone, muscle wasting, and difficulty learning to walk and talk. Onset symptoms in older children and adults include deterioration of intellectual performance, and behavioral or psychiatric problems. Blindness, seizures, and paralysis occur as the disease progresses.

•Alexander’s disease, which usually begins in infancy (six to 24 months of age) and affects mostly males. Initial signs are physical and mental retardation and as the disease progresses, enlargement of the brain and

K E Y T E R M S

Arteriopathy—Damage to blood vessels.

Ataxia—A deficiency of muscular coordination, especially when voluntary movements are attempted, such as grasping or walking.

Bile acids—Steroid acids such as cholic acid that occur in bile, an alkaline fluid secreted by the liver and passed into a part of the small intestine where it aids in absorption of fats.

Bile alcohol—A steroid acid with an alcohol group attached.

Cataract—A clouding of the eye lens or its surrounding membrane that obstructs the passage of light resulting in blurry vision. Surgery may be performed to remove the cataract.

Dementia—A condition of deteriorated mental ability characterized by a marked decline of intellect and often by emotional apathy.

Hypomyelination—The death of myelin on a nerve or nerves.

Ischemic attack—A period of decreased or no blood flow.

Leukoencephalopathy—Any of various diseases, including leukodystrophies, affecting the brain’s white matter.

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

Subcortical infarcts—Obstruction of nerve centers below the cerebral cortex of the brain.

head, spasticity, and seizures. In children and adults, symptoms are the same but occur less frequently and progress more slowly.

•CACH is usually diagnosed in infancy and initial symptoms include motor and speech difficulties that progressively worsen. Later symptoms include difficulty swallowing, seizures, and coma.

•CADASIL can be diagnosed in children and adults but usually shows up at around age 45. The initial symptom is usually migraine headaches, followed in about 10 years by ischemic attacks and small strokes followed by mood disturbances and dementia. Epilepsy sometimes occurs.

•CTX may present initial symptoms of cataracts, mild mental retardation, fatty tumors (called xanthomas) in

Leukodystrophy

Leukodystrophy

tendons, especially the Achilles tendon or heel cord. Later symptoms include seizures, emotional or psychiatric disturbances, and impaired motion or muscle movement.

•Ovarioleukodystrophy syndrome usually has onset symptoms of walking difficulties and/or mental retardation.

•Van der Knapp syndrome can have onset at or shortly after birth with the symptom of an extremely enlarged head. But onset usually occurs between ages four and five with initial symptoms of cerebella ataxia followed by spasticity. Later symptoms include mental slowing and learning problems and sometimes epileptic seizures and severe walking impairment.

Diagnosis

Leukodystrophies are occasionally misdiagnosed as muscular dystrophy, since they all are neurological disorders involving white matter. Genetic testing is usually in order for all leukodystrophies except Alexander’s disease and Van der Knapp syndrome for which the specific genetic abnormalities are unknown. A nerve conduction velocity (NCV) test is sometimes used to evaluate nerve damage in people with metachromatic leukodystrophy. The NCV test sends small electrical shocks through one end of a nerve. The time it takes to travel to the other end of the nerve is measured to help determine the severity of nerve damage. Diagnosis of CTX is made by measuring the levels of bile alcohol in the blood or urine, or of cholestanol in the blood. Cholestanol is similar chemically to cholesterol but can be distinguished from it by special chemical tests. MLD and Van der Knapp syndrome diagnosis are usually made by a brain imaging scan called magnetic resonance imaging (MRI). A series of biochemical tests is sometimes used to diagnose MLD.

Treatment and management

With the exception of CTX, none of the leukodystrophies covered here are treatable. In some of the disorders, specific symptoms can be treated. For example some infections associated with MLD, such as pneumonia, can be treated with antibiotics. In ovarioleukodystrophy syndrome, ovarian insufficiency can be treated with hormone replacement therapy. But there are no treatments available for most of the conditions associated with leukodystrophies, such as mental retardation, dementia, deterioration of speech, vision, and mobility, and degeneration of myelin (white matter). In CTX, administration of certain bile acids, especially chenodo-

deoxycholic acid, can prevent further progression of the disorder and in some cases may bring improvement.

Prognosis

The prognosis varies between leukodystrophy types but overall, most people with leukodystrophy can expect a shortened life span. Infants with Alexander’s disease generally do not live past the age of five or six. Infants with metachromatic leukodystrophy (MLD) usually do not live past age 10. In children and adults, Alexander’s disease and MLD progress more slowly but life expectancy is still shortened. Life expectancy with CACH is also shortened, with few people living beyond age 40 years. CADASIL progresses slowly but death occurs on average about 21–22 years after onset of symptoms. Life expectancy is closer to normal with CTX provided it is diagnosed and treated early. Ovarioleukodystrophy is a relatively newly identified disorder and there is not enough information available to make a prognosis of life expectancy, other than to say it is probably reduced. The average life expectancy is also unknown for Van der Knapp syndrome; several patients have died in their 20s but others are still alive in their 40s.

A number of government agencies and private foundations are currently funding research into many of the leukodystrophies, including identifying the cause of individual disorders, developing therapies to prevent disease progression, and to prevent onset of disease. However, little research is being done on therapies to repair damage already done by the disorders, or of restoring functions lost because of the disorders, according to The Myelin Project, a private research foundation.

Resources

BOOKS

Scheltens, P. White Matter Disease. Basel, Switzerland: S.

Karger Publishing AG, 1999.

ORGANIZATIONS

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

.rarediseases.org .

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

The Myelin Project. http://www.myelin.org .

Delayed Myelin. Myelin Associated Infant-Childhood Development Disorders. http://www.delayedmyelin

.homestead.com .

Ken R. Wells

I Li-Fraumeni syndrome

Definition

Li-Fraumeni syndrome (LFS) is a hereditary condition in which individuals have an increased risk for developing certain kinds of tumors. The characteristic tumors of LFS are adrenocortical carcinoma, breast cancer, brain cancer, leukemia and sarcoma. Li-Fraumeni syndrome has previously been known as the sarcoma, breast, leukemia and adrenal gland (SBLA) syndrome.

Description

Li-Fraumeni syndrome is an inherited condition that is associated with a significantly increased risk for developing certain kinds of cancer. It is classified as a hereditary cancer syndrome and was first described in 1969 by two physicians, Dr. Li and Dr. Fraumeni. Hereditary cancer syndromes typically result in multiple family members developing cancer, in family members developing the same kind(s) of cancer, in family members developing cancer at a young age, and in family members developing more than one primary cancer. In contrast, most people who develop cancer are diagnosed later in life, such as in their sixties and seventies, and do not have multiple close family members, such as a parent and/or siblings, who have developed the same kind of cancer.

Five cancers are characteristic of LFS. These five cancers are adrenocortical carcinoma, breast cancer, brain cancer, leukemia and sarcoma. Other types of cancer such as melanoma, colon cancer and stomach cancer have been seen in families with LFS, but as of 2001, it is not certain whether these tumors are truly a part of LFS. A brief description of the five characteristic cancers follows.

Adrenocortical carcinoma is a rare cancer affecting a specific part of the adrenal gland called the adrenal cortex. There are two adrenal glands and each one sits on the upper part of a kidney. Adrenal glands produce hormones and if a cancer is present, more hormones may be produced resulting in symptoms. In LFS, adrenocortical carcinomas typically develop in childhood.

Brain cancer refers to a tumor developing in the brain. There are different kinds of tumors that may develop in the brain; the type depends upon the part of the brain involved. The brain tumors that occur in LFS tend to develop in young adulthood although they may develop at any age.

Breast cancer is a cancer affecting the breast, and in LFS, women are often diagnosed with breast cancer in their twenties, thirties, and forties. Although breast cancer in men is rare, it does occur both within families with LFS and in the general population.

Leukemia refers to cancer of the blood. There are more than one type of leukemia; the type depends upon the kind of blood cell involved and whether the cancer is fast (acute) or slow (chronic) growing. Overall, acute lymphocytic leukemia (ALL) is the most common leukemia in children and acute myelogenous leukemia (AML) is common in young adults. Chronic myelogenous leukemia (CML) is a common leukemia in older individuals. Li-Fraumeni syndrome is typically associated with acute leukemias and are most often diagnosed in children, adolescents and young adults.

Sarcoma refers to a soft-tissue tumor, meaning that the tumor has developed in bone, muscle, or connective tissue. Osteosarcoma refers to a sarcoma that has developed in the bone. Rhabdomyosarcoma is a sarcoma that has developed in the muscle. Both of these sarcomas are associated with LFS and typically are diagnosed in children and in adults before the age of 35 years. A third type of sarcoma, Ewing’s sarcoma, is another type sarcoma arising in bone, but it is not associated with LFS.

An individual inheriting the familial LFS gene alteration has a significantly increased risk for developing one of the five characteristic cancers in his/her lifetime. This risk is about 85–90% by age 60, meaning that 85–90 out of 100 individuals inheriting a LFS gene alteration will develop one of the five characteristic cancers by the time he/she reaches 60 years of age. Much of this risk occurs in childhood through middle adulthood with the majority of individuals developing cancer by the time they reach 30 years of age.

Genetic profile

Li-Fraumeni syndrome follows autosomal dominant inheritance meaning that every individual diagnosed with LFS has a 50% (1 in 2) chance of passing on the condition to each of his/her children. Nearly every individual inheriting the LFS gene alteration will develop at least one of the characteristic tumors. However, not every family member inheriting the LFS gene alteration will develop the same kind of tumor. Additionally, some family members may develop more than one tumor whereas other family members may develop one tumor. For example, a family history may include a father who was diagnosed with a brain tumor at age 50, a daughter who was diagnosed with an adrenocortical carcinoma at age three and breast cancer at age 43 years, and a granddaughter who was diagnosed with sarcoma at age seven.

The majority of families with LFS have an alteration in a gene located on the short arm of chromosome 17 at location p53. There may be another gene(s) involved in LFS but as of 2001, no other gene has been identified in families in LFS.

syndrome Fraumeni-Li

Li-Fraumeni syndrome

K E Y T E R M S

Chemotherapy—Treatment of cancer with synthetic drugs that destroy the tumor either by inhibiting the growth of the cancerous cells or by killing the cancer cells.

Mammography—X rays of the breasts; used to screen for breast cancer.

Metastasis—The spreading of cancer from the original site to other locations in the body.

Primary tumor—The organ or tissue where the tumor began.

Radiation therapy—Treatment using high-energy radiation from x-ray machines, cobalt, radium, or other sources.

Stage—The extent of the tumor. Tests will be done to determine if the tumor is localized to the organ or if it has spread to the lymph nodes and/or other organs. Treatment depends upon the stage of the cancer.

Tumor—An abnormal growth of cells. Tumors may be benign (noncancerous) or malignant (cancerous).

Demographics

Li-Fraumeni syndrome is a rare condition. About 300 families worldwide have been reported in the medical literature, however, not all families with LFS have been published in the medical literature. Males and females are equally affected.

Signs and symptoms

General symptoms of cancer include unexplained weight loss, weakness, fatigue, and pain. Symptoms specific to each characteristic tumor are listed below. It should be noted that the same kind of cancer may cause different symptoms in different people as well as that individuals with LFS may develop other kinds of cancer; consequently, any new and/or unusual symptom should be evaluated by a physician.

Adrenocortical carcinomas may cause abdominal pain. In some cases, the tumor causes extra hormones to be produced, and if so, the individual may experience high blood pressure, diabetes, deepening of the voice, swelling of the sexual organs and/or breasts or growth of hair on the face.

Brain cancer may result in a number of symptoms including vomiting, seizures, headaches, behavioral

changes or problems, changes in eating or sleeping patterns, fatigue or clumsiness.

Breast cancer typically results in a lump. Occasionally, the nipple may invert or the skin over the lump may dimple. In rare cases, the breast may suddenly become red and swollen. Breast cancer can be identified before symptoms develop by the use of mammography.

Leukemia may result in unusual bruising, a pale appearance and/or recurrent infections. Little red or purple spots, called petechiae, may develop on the skin.

Sarcomas result in different symptoms depending upon the type of sarcoma. Osteosarcomas often lead to swelling and pain, symptoms that may be confused with an injury. Rhabdomyosarcomas cause a lump to develop and swelling.

Diagnosis

Evaluation of a family history for LFS requires a detailed three-generation family tree as well as medical records and/or death certificates to confirm or clarify the tissues involved as well as the age of the individual at the time of his/her diagnosis. Diagnosis of LFS depends upon the types of tumors family members have developed and the ages at which the tumors were diagnosed. A set of criteria for diagnosing LFS has been established.

A family may not meet the criteria for diagnosis of LFS but may have features that suggest LFS. Families such as these may be said to be “Li-Fraumeni-like” (LFL). Two sets of criteria have been developed for LFL, which like the diagnostic criteria, are based upon the high incidence of tumors in these families and the earlier ages of diagnosis.

Caution needs to be used when evaluating a family history of early-onset breast cancer, i.e. diagnosis in the twenties and thirties, since several other genes besides p53 are known to result in women having an increased risk for developing breast cancer at young ages. The clinical features of these other genes need to be taken into account and evaluated for while evaluating a family for LFS.

Genetic testing for p53 gene mutations is available and provides an additional method for making a diagnosis. It may be offered to an individual who has developed one of the tumors characteristic of LFS and who has a family history that meets the diagnostic criteria or strongly suggests LFS in order to confirm the diagnosis of LFS in the family. This is referred to as diagnostic testing. If a mutation is identified, the positive test result provides proof of the diagnosis. If no mutation is identified, this negative test result does not necessary remove the diagnosis of LFS. Genetic testing may not identify a

mutation for two reasons. First, laboratory techniques are not perfect and not every mutation in the p53 gene has been or can be identified; as of 2001, about 70 to 80% of mutations are identifiable. Second, there may be another gene(s) involved in LFS, but as of 2001, a second gene has not been identified and it is not known for certain whether there is second gene involved in LFS.

Genetic testing for LFS may be offered for a second reason. Genetic testing may be offered to an individual who has no personal history of cancer but whose family history meets the diagnostic criteria for LFS or is strongly suggestive of LFS. It is usually offered in order to determine this individual’s risk for developing cancer and to help with decisions regarding medical screening. Genetic testing in this case is referred to as predictive or presymptomatic genetic testing. Predictive genetic testing should not be done unless a p53 genetic alteration has already been identified in an affected family member.

Genetic testing for diagnostic and predictive purposes is associated with significant risks and limitations, uncertain benefits and is best done with a geneticist (a doctor specializing in genetics) and/or genetic counselor knowledgeable about LFS and the implications of genetic testing. As of 2001, predictive genetic testing for LFS does not clearly provide a benefit for all family members at-risk for inheriting a familial p53 gene alteration since medical screening and prevention methods are not available for the tumors associated with LFS.

Prenatal diagnosis of LFS is available only if a p53 genetic alteration has already been identified in the family. Prenatal diagnosis of LFS is considered to be predictive genetic testing and therefore, the issues surrounding predictive genetic testing exist in this situation. An additional issue is how is the test result will be used with regard to continuation of the pregnancy. Individuals considering prenatal diagnosis of LFS should confirm its availability prior to conception.

Treatment and management

There is no cure or method for preventing LFS. Treatment depends upon the tumor(s) an individual develops. An individual does not require treatment until a tumor develops and then, the treatment will be specific to the type of tumor that has developed. An individual without symptoms, should, as indicated below, undergo regular medical check-ups.

In general, tumors are treated by surgery, chemotherapy and/or radiation therapy. Adrenocortical carcinomas and breast cancers, depending upon the stage of the tumor, use one or more of these treatments. Brain cancer is treated by surgery and/or radiation. In some cases, chemotherapy is also used. Leukemia is primarily treated

TABLE 1

Age of onset for cancers associated with

Li-Fraumeni syndrome

by chemotherapy. In some cases, bone marrow transplantation is used. Osteosarcoma is treated by surgery. Rhabdomyosarcoma is treated by surgery, chemotherapy and radiation therapy.

There are no proven methods of screening for or preventing cancer in individuals with LFS, other than perhaps breast cancer. It is very important that an individual’s physician is aware of the family history and the cancer risk. It has been suggested that children of a parent with LFS be followed by having a complete physical examination, urinalysis, complete blood count (CBC) and abdominal ultrasound examination once each year. For adults at-risk for having inherited a familial p53 gene alteration, it has been suggested that they undergo a complete physical examination with skin, nervous system and rectal examinations once a year and that women undergo a clinical breast examination every six months and mammography once a year. As of 2001, there is controversy concerning the use of mammography in women with LFS because of some suggestion that p53 gene alterations are sensitive to radiation. In general, an individual may decrease his/her chance of developing cancer by not smoking, exercising on a regular basis, eating a healthy diet, limiting sun exposure and limiting his/her alcohol intake. Lastly, an individual with or at-risk for LFS should not delay seeing his/her physician if he/she notices a new or unusual symptom.

Prognosis

An individual who has LFS has a very high chance of developing a cancerous tumor by the time he/she is 60 years old. In contrast, individuals in the general population have about a 2% risk for developing cancer. The cancers associated with LFS each have a different prognosis and so, an individual’s prognosis is highly dependent upon the type of cancer he/she has developed. In some cases, prognosis is associated with how early the cancer has been found. For example, breast cancer found early has a better prognosis than breast cancer found later. In general, the cancers typically seen in LFS are curable if caught early. For this reason, regular medical screening is

syndrome Fraumeni-Li

Limb-girdle muscular dystrophy

dystrophy muscular girdle-Limb