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.

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

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 important. Prognosis may also be affected by the individual's overall health; consequently, being healthy and engaging in healthy behaviors may increase the chances of a good outcome.

Resources

BOOKS

Buckman, Robert. What you really need to know about cancer:A comprehensive guide for patients and their families. Baltimore: The Johns Hopkins University Press, 1995.

Offit, Kenneth. "Li-Fraumeni Syndrome". In Clinical CancerGenetics: Risk Counseling and Management. New York: Wiley-Liss, 1998, pp.157-162.

PERIODICALS

National Institute of Health: National Cancer Institute. When someone in your family has cancer. (December 1995).

National Institute of Health: National Cancer Institute. Taking time: Support for people with cancer and the people who care about them. (January 1997).

National Institute of Health: National Cancer Institute. Understanding gene testing. (December 1995).

ORGANIZATIONS

National Cancer Institute. Office of Communications, 31 Center Dr. MSC 2580, Bldg. 1 Room 10A16, Bethesda, MD 20892-2580. (800) 422-6237. <http://www.nci.nih.gov>.

National Cancer Institute. Office of Communications, 31 Center Dr. MSC 2580, Bldg. 1 Room 10A16, Bethesda, MD 20892-2580. (800) 422-6237. <http://cancernet.nci.nih.gov>.

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

National Cancer Institute. "Kids Home." CancerNet. <http://cancernet.nci.nih.gov/occdocs/KidsHome.html>.

National Cancer Institute. "Young people with cancer: Handbook for parents." CancerNet.<http://cancernet.nci.nih.gov/Young_People/yngconts.html>.

OncoLink. University of Pennsylvania. <http://www.oncolink.upenn.edu/>.

Schneider, K. A., and F. P. Li. "Li-Fraumeni Syndrome." Gene-Clinics. Univeristy of Washington, Seattle. <http://www.geneclinics.org/>.

Cindy L. Hunter, MS, CGC