Instability Syndromes

Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies. The following chromosome instability syndromes are known: • • • • •

Ataxia telangiectasia Ataxia telangiectasia-like disorder Bloom syndrome Fanconi anaemia Nijmegen breakage syndrome

Ataxia-telangiectasia Ataxia-telangiectasia is a rare inherited disorder that affects the nervous system, immune system, and other body systems. This disorder is characterized by progressive difficulty with coordinating movements (ataxia) beginning in early childhood, usually before age 5. Affected children typically develop difficulty walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). The movement problems typically cause people to require wheelchair assistance by adolescence. People with this disorder also have slurred speech and trouble moving their eyes to look side-to-side (oculomotor apraxia). Small clusters of enlarged blood vessels called telangiectases, which occur in the eyes and on the surface of the skin, are also characteristic of this condition. Affected individuals tend to have high amounts of a protein called alpha-fetoprotein (AFP) in their blood. The level of this protein is usually increased in the bloodstream of pregnant women. The effect of abnormally high levels of AFP in people with ataxiatelangiectasia is unknown. People with ataxia-telangiectasia often have a weakened immune system, and many develop chronic lung infections. They are also at an increased risk of developing cancer, particularly cancer of blood-forming cells (leukemia) and cancer of immune system cells (lymphoma). Affected individuals are very sensitive to the effects of radiation exposure, including medical x-rays. Although people with ataxia-telangiectasia usually live into adulthood, their life expectancy is reduced. Ataxia-telangiectasia occurs in 1 in 40,000 to 100,000 people worldwide Ataxia-telangiectasia is inherited in an autosomal recessive pattern, which means both copies of the ATM gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition. About 1 percent of the United States population carries one mutated copy and one normal copy of the ATM gene in each cell. Although ATM mutation carriers do not have ataxiatelangiectasia, they are more likely than people without an ATM mutation to develop

cancer, particularly breast cancer. Carriers of a mutation in the ATM gene also may have an increased risk of heart disease and diabetes. Bloom syndrome Bloom syndrome is an inherited disorder characterized by a high frequency of breaks and rearrangements in an affected person's chromosomes. People with Bloom syndrome are much smaller than average, and often have a high-pitched voice and characteristic facial features including a long, narrow face; small lower jaw; and prominent nose and ears. They tend to develop pigmentation changes and dilated blood vessels in the skin, particularly in response to sun exposure. These changes often appear as a butterflyshaped patch of reddened skin on the face. The skin changes may also affect the hands and arms. Other features of the disorder may include intellectual disabilities, chronic lung problems, diabetes, and immune deficiency that leads to recurrent pneumonia and ear infections. Men with Bloom syndrome usually do not produce sperm, and as a result are unable to father children (infertile). Women with the disorder generally experience menopause earlier than usual. Chromosome instability in Bloom syndrome results in a high risk of cancer in affected individuals. Affected individuals develop the full range of cancers found in the general population, but the cancers arise unusually early in life. People with Bloom syndrome may be first diagnosed with cancer at about 25 years old. Bloom syndrome is a very rare disorder in most populations, and its overall frequency is unknown. It is more common in people of Central and Eastern European (Ashkenazi) Jewish background, among whom 1 in 48,000 are affected. Approximately one third of people with Bloom syndrome are of Ashkenazi Jewish descent. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Fanconi anaemia http://www.cancerindex.org/ccw/fanconi.htm http://en.wikipedia.org/wiki/Fanconi_anemia Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi.[1][2] It should not be confused with Fanconi syndrome, a kidney disorder also named after Fanconi.

FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C.

Nijmegen breakage syndrome (NBS). The NBN gene provides instructions for making a protein called nibrin. This protein is involved in several critical cellular functions, including the repair of damaged DNA.Disorders caused by mutations in the NBN gene At least eight mutations in the NBN gene have been identified in people with a condition called Nijmegen breakage syndrome (NBS). This condition results when a person is born with two altered copies of the NBN gene in each cell. Nijmegen breakage syndrome is characterized by slow growth and short stature, an abnormally small head size (microcephaly), mild to moderate intellectual disability, distinctive facial features such as a sloping forehead and prominent nose, and recurrent respiratory infections. About 50 percent of people with this condition also develop cancer, most commonly a cancer of immune system cells (lymphoma). Each of the mutations that cause this condition leads to the production of an abnormally short version of the nibrin protein. The defective protein is missing important regions, preventing it from responding to DNA damage effectively. As a result, breaks in DNA are not repaired properly and genetic damage can accumulate. This buildup of mistakes in DNA can trigger cells to grow and divide abnormally, increasing the risk of cancer in people with Nijmegen breakage syndrome.