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

V Leiden thrombophilia is suspected in individuals who have had multiple blood clots in the veins (venous thrombosis), more than three unexplained miscarriages, or a family history of individuals with multiple blood clots in the blood vessels.

Diagnosis

Diagnosis of factor V Leiden thrombophilia can be done through a blood coagulation screening test or DNA analysis of the gene that codes for factor V.

The blood coagulation screening test uses the breakdown protein APC in a resistance study to see how quickly the factor V is broken down as compared to other blood clotting factors. An individual with factor V Leiden thrombophilia has factor V that is resistant or much slower to being broken down by the APC protein. At this time there are two types of APC resistance screening tests for factor V Leiden thrombophilia. The preferred test is the “modified second generation” APC resistance study because an extra step in the testing (dilution by plasma without factor V) makes it almost 100% accurate even in pregnant women and patients being treated by medications such as heparin and warfarin.

The DNA or molecular analysis examines the F5 gene to learn if the gene is altered or mutated.

Prenatal diagnosis is not offered routinely because the disorder is fairly mild and effective treatment is available.

Treatment and management

The treatment and management of individuals affected by factor V Leiden thrombophilia is focused on prevention of floating blood clots (thrombosis) and thromboembolism. The management of affected individuals should be overseen by a hematologist who specialized in blood clotting disorders and a general practitioner or internist who can work closely with the hematologist.

At different times of life, different specialists may need to be added. For example, when pregnant, a perinatologist or high-risk obstetrician should work with the hematologist during pregnancy. Additionally, individuals who have had a deep vein clot or stroke may need to consult a vascular specialist and/or neurologist.

The physicians managing an affected individual’s care should discuss with them the timing, risks, and benefits of taking birth control pills and taking “blood thinning” anticoagulant medications like warfarin, aspirin, and heparin. Individuals affected by factor V Leiden

K E Y T E R M S

Deep vein thrombosis—A blood clot in one of the systemic veins deep in the body.

Heterozygous—Having two different versions of the same gene.

Homozygous—Having two identical copies of a gene or chromosome.

Thromboembolism—A condition in which a blood vessel is blocked by a free-floating blood clot carried in the blood stream.

Venous thrombosis—A condition caused by the presence of a clot in the vein.

thrombophilia should also be examined to make sure they do not have other blood clotting disorders in addition to factor V Leiden thrombophilia.

Prognosis

Individuals affected by factor V Leiden thrombophilia have a wide range of symptoms and signs. Some individuals affected by factor V Leiden thrombophilia will never develop physical signs and symptoms of the disorder. Other individuals will be more severely affected. Most affected individuals will not experience their first clotting event until adulthood. However, individuals with homozygous factor V Leiden thrombophilia have a significantly increased risk to have symptoms of the disease at a younger age. Treatment and close management of the disorder can reduce the risk of thromboembolism significantly.

Resources

PERIODICALS

Major, D. A., et al. “Cardiovascular Implications of the Factor V Leiden Mutation.” American Heart Journal (August 2000): 189-195.

ORGANIZATIONS

Thrombophilia Support. http://www.fvleiden.org .

WEBSITES

“Factor V Leiden Thrombophilia.” GeneClinics. http://www

.geneclinics.org/profiles/factor-v-leiden/index.html . Thrombophilia Support Page. http://www.fvleiden.org . “Venous Thrombosis and Factor V (Leiden) Mutation.” Genetic

Drift Newletter 14 (Spring 1997). http://www.mostgene

.org .

Dawn A. Jacob, MS

thrombophilia Leiden V Factor

Fahr disease

I Fahr disease

Definition

Fahr disease is a rare, progressive neurological disorder that is often hereditary. Characterized by deposits of calcium in the basal ganglia and other parts of the brain, Fahr disease causes worsening dementia and the loss of routine motor skills, among other symptoms.

Description

Though calcium is important for good health, this mineral can have harmful effects when it appears in parts of the body where it does not belong. In Fahr disease, abnormal deposits of calcium build up in a region of the brain called the basal ganglia (mainly in a section called the globus pallidus), as well as in other parts of the brain. The basal ganglia is the technical name given to clusters of nerve cells that help to initiate and control movements of the body—for example, reaching for a cup of coffee or taking a step forward while walking. The presence of these calcium deposits (referred to as calcifications) interferes with the working of the brain, causing a variety of debilitating mental and physical symptoms that worsen over time. Aside from the basal ganglia, the calcium deposits associated with Fahr disease often appear in other areas of the brain such as the cerebral cortex.

Two important effects of the disease are dementia and the loss of learned motor skills. People affected by Fahr disease may become overly forgetful and easily confused or disoriented. They have trouble performing relatively simple tasks that require basic hand-eye coordination. Most people with the disease experience slurred speech and problems involving involuntary movements or poor coordination. In addition, personality changes and disorders of mood may develop. In one study of 18 people with Fahr disease, half of the participants had symptoms of obsessive-compulsive disorder, major depression, or bipolar disorder. People with Fahr may have psychotic symptoms, including hallucinations (visual and auditory), a distorted perception of reality, and paranoid delusions.

As the disease progresses, it causes an increasing degree of paralysis. Muscles become stiff and physical movement is restricted. Aside from these symptoms, people with Fahr disease may experience specific movement disorders: slow, twisting movements of the hands and feet (athetosis) and jerky, rapid movements that resemble spasms (chorea). Vision may also be affected. Because the disease can weaken nerves that carry signals from the eyes to the brain, people with Fahr disease may experience partial or almost complete vision loss. Ear infections have also been reported.

The underlying cause of Fahr disease is unknown. For this reason, it is described as an idiopathic disorder. Fahr disease is often referred to in the medical literature as idiopathic basal ganglia calcification (IBGC). Less common names for the disease include cerebrovascular ferrocalcinosis, non-arteriosclerotic cerebral calcifications, and striopallidodentate calcinosis.

Genetic profile

Fahr disease often runs in families and is believed to be inherited either as a recessive or dominant trait. In the recessive version of Fahr disease, a person must inherit the same abnormal gene (associated with Fahr disease) from both parents in order to develop the disease. Therefore, a child who receives only one recessive gene for the disease can become a carrier but will not usually develop symptoms. In the dominant version of Fahr disease, a person may develop the condition after receiving just one copy of the abnormal gene from either the mother or father.

Researchers studying a particular family affected by Fahr disease over several generations discovered a pattern regarding the age at which the condition strikes. The results of this medical study indicated that each generation with Fahr developed symptoms at an earlier age than previous generations, a phenomenon described as “genetic anticipation.” The family (referred to as a “kindred”) being analyzed in this study was affected by the dominantly inherited version of the disease.

While studying this kindred, researchers located a gene believed to play a role in the disorder. The gene was named IBGC1 (“IBGC” is short for “idiopathic basal ganglia calcification,” another name for Fahr disease). The gene location was identified as 14q, situated on the long arm (called q) of chromosome 14. Despite this finding, more research is necessary to determine the identity and nature of the gene or genes associated with Fahr disease.

Aside from inherited forms, Fahr disease can occur sporadically for reasons that are not well understood. Some medical studies suggest that sporadic cases of Fahr disease may result from an as-yet unidentified infection that affects the fetus in the womb.

Demographics

Fahr disease, which appears to affect men and women equally, can appear at any stage of life, from infancy to adulthood. Some people diagnosed with the disease have no family history of the condition, while in many cases Fahr disease runs in families and affects members of several generations. In people with dominantly inherited Fahr disease, symptoms usually appear

anywhere between the ages of 30 and 60. The recessive form of Fahr disease emerges at a younger age, between infancy and young adulthood.

Signs and symptoms

People with Fahr disease have abnormal calcium deposits in the basal ganglia, primarily in the globus pallidus region, and often in other parts of the brain. Loss of brain cells in these areas also occurs. The results of electrocardiogram (ECG) studies, which monitor heartbeats, are often abnormal in people with Fahr disease. Other signs include malfunctioning parathyroid glands and low blood calcium levels.

The disease causes a variety of physical and psychological symptoms. The head of a person with Fahr disease is often smaller and rounder than normal. The condition causes worsening dementia and loss of routine motor skills. Muscle stiffness, movement disorders, and paralysis may occur. Speech often becomes slurred. In some cases, Fahr disease causes vision problems and ear infections. Symptoms of Parkinson’s disease may develop as well.

Diagnosis

In simple terms, Fahr disease is diagnosed when calcifications in the basal ganglia are associated with slurred speech, movement disorders, and other specific symptoms. Special imaging procedures such as a CT scan can detect the presence of calcium deposits. Symptoms can be determined by physical and psychological examinations. Friends or family members with relevant observations of the patient’s behavior can also be helpful. Blood tests may be recommended to evaluate blood calcium levels and the parathyroid glands. The appearance of Parkinson-like symptoms is not essential to a diagnosis of Fahr disease.

In the absence of other factors, calcium deposits in the basal ganglia do not necessarily indicate the presence of Fahr disease. Such calcifications may be due to a metabolism disorder, infectious disease, or a genetic disorder other than Fahr disease. In fact, sometimes these calcifications may be present without producing any symptoms or harmful effects, especially in people older than age 60.

Treatment and management

There is no cure for Fahr disease, which worsens over time. The process of calcification cannot be stopped or reversed. Where possible, clinicians focus on alleviating its various mental and physical effects. These may vary to some degree depending on the individual, even among members of the same family. Lithium carbonate, for example, may be recommended to control psychotic

K E Y T E R M S

Calcification—A process in which tissue becomes hardened due to calcium deposits.

Cerebral cortex—The outer surface of the cerebrum made up of gray matter and involved in higher thought processes.

Cerebrum—The largest section of the brain, which is responsible for such higher functions as speech, thought, vision, and memory.

Computed tomography (CT) scan—An imaging procedure that produces a three-dimensional picture of organs or structures inside the body, such as the brain.

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

Idiopathic—Of unknown origin.

Neurological—Relating to the brain and central nervous system.

Parathyroid glands—A pair of glands adjacent to the thyroid gland that primarily regulate blood calcium levels.

symptoms, while antidepressant medications are often used to combat depression. Ear infections associated with Fahr disease can be treated with antibiotics and pain medication.

Prognosis

Due to its damaging effects on the brain and nervous system, Fahr disease is eventually fatal.

Resources

BOOKS

Victor, Maurice, et al. Principles of Neurology. 7th ed. New York: McGraw-Hill, 2001.

PERIODICALS

Geschwind, D. H., et al. “Identification of a Locus on Chromosome 14q for Idiopathic Basal Ganglia Calcification (Fahr Disease).” American Journal of Human Genetics 65 (1999): 764-772.

Lauterbach, E. C., et al. “Neuropsychiatric Correlates and Treatment of Lenticulostriatal Diseases: A Review of the Literature and Overview of Research Opportunities in Huntington’s, Wilson’s, and Fahr’s Diseases. A report of the ANPA Committee on Research. American Neuropsychiatric Association.” Journal of Neuropsychiatry and Clinical Neurosciences 10 (1998): 249-66.

disease Fahr

Familial adenomatous polyposis

Rosenblatt, A., and I. Leroi. “Neuropsychiatry of Huntington’s Disease and Other Basal Ganglia Disorders.” Psychosomatics 41 (2000): 24-30.

ORGANIZATIONS

National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424.http://www.ninds.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

Association of Birth Defect Children, Inc.http://www.birthdefects.org .

Greg Annussek

I Familial adenomatous polyposis

Definition

Familial adenomatous polyposis is an inherited condition that typically presents with extensive adenomatous polyps of the colon. These polyps often develop into colorectal cancer in early adult life. Other symptoms are often present as well. These signs include polyps in the upper gastrointestinal tract, malignancies in the brain or thyroid, pigmented retinal lesions, and osteomas.

Description

Familial adenomatous polyposis (FAP) was first clearly described as a dominantly inherited colorectal cancer susceptibility by Lockhart-Mummery in an article published in 1925. FAP has since served as a paradigm for hereditary cancer and has taught much about the diagnosis, surveillance, and management of colon cancer. It is one of the most clearly defined and well understood of the inherited colon cancer syndromes. FAP is thought to account for approximately 1% of all cases of colorectal cancer.

FAP is a disorder that is characterized by the development of hundreds to thousands of glandular colorectal tumors called adenomas or adenomatous polyps, meaning that they are benign growths made of the tissue that lines the inside of the colon. They are described as polyps because they protrude from mucous membranes. In FAP, these tumors generally develop by the second or third decade of life. They are found in the internal lining of the

colon and the rectum, with a particular affinity for the left side of the colon or the rectosigmoid. By themselves, these polyps are benign but they have the ability to become malignant, leading to colorectal cancer. If the polyps are not treated properly, it is almost certain that a person affected with FAP will develop colorectal cancer by the age of 40.

Other clinical findings that may be associated with FAP include polyps in the upper gastrointestinal tract, extraintestinal manifestations such as osteomas and epidermoid cysts, desmoid formation, retinal lesions, and malignant changes in other organs. Symptoms are thought to manifest anywhere between the ages of 16 and 50 years.

FAP is also known as familial polyposis coli (FPC) and adenomatous polyposis coli (APC). Gardner syndrome and Turcot syndrome are variants of FAP. Gardner syndrome is used to describe patients with FAP and the extracolonic symptoms of osteomas, soft tissue tumors, desmoids, and dental abnormalities. Turcot syndrome is used when FAP is seen in conjunction with tumors of the central nervous system called medulloblastomas (cerebral tumors that occur in childhood). Attenuated FAP (AFAP) is another variant of FAP. In this condition, individuals present with fewer polyps, usually fewer than 100 in number and often in the right colon. Patients with AFAP may have a later onset of cancer than those with classic FAP.

Genetic profile

FAP is inherited in an autosomal dominant pattern; thus, an affected person has a 50% chance of passing the disease on to each of his or her children. It is almost 100% penetrant, meaning that nearly everyone who carries the gene mutation will show signs of the disorder. The majority of patients with FAP inherit the mutation from one of their parents. However, in approximately 25% of cases, there is no family history of the disorder and FAP occurs because of a new mutation in the affected individual.

The majority of cases of FAP are due to mutations of the APC gene, located on the long arm (or “q” arm) of chromosome 5. This gene encodes a protein that is important in cell adhesion and signal transduction. More than 300 different APC mutations have been described in FAP patients. Most APC mutations seen in individuals with FAP result in translation of a protein that is shorter than normal. This shortened protein cannot function properly.

Studies have shown that the type and location of the APC mutation seems to correlate to the clinical symptoms that a person manifests. For example, if the muta-

tion is located near the center of the gene, colonic polyps tend to be more dense and numerous. A mutation towards the ends of the gene often leads to polyps that are fewer and more sparse, as in attenuated FAP. Additionally, mutations at one particular end (the 3 end) of the APC gene seem to be associated with a higher risk of desmoid formation. However, it is known that family members who carry identical mutations often have different clinical features. This suggests that modifying genes and/or environmental factors also influence the expression of the APC gene mutation.

The APC gene is a tumor suppressor gene, meaning that its function is to control cell growth. When APC is mutated, it does not function correctly and allows cells to grow out of control. This results in tumors that may lead to cancer. Carriers of mutations in APC inherit a germline mutation in one allele of the gene. Thus, in every one of their cells, one gene does not make the APC protein but the corresponding gene on the other chromosome continues to produce the functional protein. Thus, tumor suppression continues. However, if a somatic mutation occurs in the remaining functional gene, no APC protein is made, tumor suppression fails, and tumors develop. These somatic mutations occur in various parts of the body at various times, leading to multiple tumors forming in distinct parts of the body over a period of time. In the case of FAP, many of these tumors are confined to the colon but can occur in other organs as well.

Demographics

Approximately one of 8,000 people are affected with FAP. It is seen in all racial and ethnic groups. Both sexes are affected equally.

Signs and symptoms

Colorectal

FAP is characterized by multiple (more than 100) adenomatous polyps of the colon and rectum. These generally develop after the first decade of life but the age of onset of adenomas is variable. Fifteen percent of individuals with FAP will show these polyps by age 10, 75% by age 20, and 90% by the age of 30. More than 95% of affected individuals will have adenomatous polyps by the age of 35. Although these polyps are benign, it is inevitable that, if left untreated, at least one of the hundreds of polyps will eventually progress to cancer. The majority of cancers appear by the age of 40 and over 90% appear by the age of 45. Symptoms of polyps and/or colorectal cancer may include rectal bleeding, change in bowel habits, iron deficiency anemia, or abdominal pain.

K E Y T E R M S

Benign—A non-cancerous tumor that does not spread and is not life-threatening.

Duodenum—Portion of the small intestine nearest the stomach; the first of three parts of the small intestine.

Epidermoid cyst—Benign, cystic tumor derived from epithelial cells.

Fibroma—A non-malignant tumor of connective tissue.

Hypertrophy—Increase in the size of a tissue or organ brought on by the enlargement of its cells rather than cell multiplication.

Lipoma—A benign tumor composed of well-differ- entiated fat cells.

Malignant—A tumor growth that spreads to another part of the body, usually cancerous.

Osteoma—A benign bone tumor.

Somatic—Relating to the nonreproductive parts of the body.

Upper gastrointestinal tract

Many individuals with FAP will develop adenomas in the upper gastrointestinal tract as well. The second portion of the duodenum is particularly prone to these polyps. These adenomas are benign, as they are in the colon, but about 5–8% of patients with FAP will eventually develop cancer in this area. Duodenal cancer seems to cluster in certain FAP families while being absent in others. Adenomas of other portions of the small bowel may also occur but with lesser frequency.

In people affected with FAP, benign adenomas can also be seen in the stomach. Gastric cystic fundic gland polyps are also common. These are benign polyps that occur in the fundic gland of the stomach, an organ that secretes enzymes and mucus. It is rare for these polyps to become cancerous in individuals of Western origin. However, in Japanese and Korean families with FAP, the risk of gastric cancer is reported to be increased threeto four-fold over the general population.

Ocular, skeletal, and cutaneous

Approximately two thirds of individuals with FAP will have congenital hypertrophy of the retinal pigment epithelium (CHRPE). These lesions are typically flat, oval, and pigmented. They can be detected by an oph-

polyposis adenomatous Familial

Familial adenomatous polyposis

thalmology examination. In FAP patients, these lesions are usually multiple, bilateral, or large. CHRPE does not affect vision nor does it have the potential to become malignant. However, CHRPE is a very important finding for families with a history of FAP. If CHRPE runs in a family with FAP, all or nearly all affected individuals in the family will have this finding. It can be detected at birth and can thus identify susceptible family members at a young age.

Other manifestations of FAP include dental abnormalities, such as impacted teeth, supernumerary teeth, and congenitally missing teeth. Osteomas can occur, often in the jaw area or on the forehead. Soft tissue tumors, such as lipomas, epidermoid cysts, and fibromas, are observed in some patients with FAP as well.

Other tumors and malignancies

Abdominal desmoid tumors occur in approximately 15% of individuals with FAP. Desmoids are tumors made of connective tissue. Although they are not cancerous, approximately 10% grow very aggressively and can become life threatening. They may lead to obstruction of blood vessels, the intestine, or ureters. They may also result in abdominal distention and associated pain and discomfort. Over 70% of these tumors develop in women aged 20–40 years, suggesting a hormonal role in their development. Additionally, they occur more commonly in those who have had prior abdominal surgery. Desmoids may occur as part of classical FAP, as part of Gardner syndrome, or sporadically, without the colonic findings of FAP.

Additionally, patients with FAP are at an increased risk for cancers in organs outside of the gastrointestinal tract. These include brain tumors, thyroid tumors, and hepatoblastoma. Hepatoblastoma is a malignant tumor of the liver and occurs in approximately 1.6% of patients with FAP in the first five years of life. Tumors of the adrenal cortex, biliary tract, and pancreas have also been reported.

Diagnosis

FAP can be diagnosed clinically in any individual with greater than 100 polyps in the colon or rectum. The diagnosis is usually made via flexible sigmoidoscopy. This procedure may be done on a routine basis or to investigate possible symptoms of colon polyps and/or colorectal cancer. Flexible sigmoidoscopy involves inspecting the interior of the rectum and the sigmoid colon, or the terminal part of the colon that leads to the rectum. Once polyposis has been established, complete colonoscopy may be necessary to further evaluate the extent of the polyps. Colonoscopy is a more invasive pro-

cedure that examines the interior of the entire colon and rectum, rather than only the terminal part.

In regards to a diagnosis in someone who does not yet have colon polyps, retinoscopy, or examination of the retina, can be useful in a family where CHRPE has been associated with FAP. In these families, CHRPE is almost 100% predictive of FAP; thus, if someone shows CHRPE on an ophthalmology exam, it is very likely that he or she is affected with FAP. Although genetic testing yields more certain predictive information, retinoscopy is a relatively inexpensive and noninvasive alternative diagnostic screening measure in families with a history of FAP associated with CHRPE.

Polyps may be first detected by the passage of occult (non-visible) blood in the stool by means of fecal occult blood testing. This testing is also inexpensive and noninvasive, and if positive, could indicate that additional testing is needed.

FAP can also be diagnosed by genetic testing. This type of testing may be used to identify someone who is affected but does not yet show any symptoms of FAP. It can also confirm the diagnosis of FAP in someone who has polyposis discovered via flexible sigmoidoscopy. APC gene testing is most commonly performed by using a protein truncation test, which looks for the presence of shortened proteins caused by a mutation in the gene. This test identifies approximately 80% of those affected with FAP. The other 20% of patients likely have mutations that do not lead to a shortened protein. It is important to test an affected family member first to determine whether or not a detectable mutation is present. If a mutation is identified in this affected person, other at-risk family members can be tested for this particular mutation. However, if a mutation is not identified in the affected individual, it is likely that the mutation does not produce a shortened protein. In this case, protein truncation testing would not be informative for the rest of the family.

FAP can also be diagnosed by linkage analysis. This testing identifies approximately 95% of affected individuals, however, blood samples are required from numerous family members, including at least one affected individual. Thus, logistically, this procedure is more complicated than the protein truncation testing mentioned above.

Treatment and management

There is no treatment for FAP because the genetic abnormality cannot be fixed. Management focuses on routine surveillance of at-risk and affected individuals for early detection and treatment of colonic polyps and other manifestations.

For individuals diagnosed with FAP, either clinically or via linkage analysis or protein truncation testing, an annual sigmoidoscopy must be performed beginning around the age of 10 years. Sigmoidoscopy is preferred because it is less invasive, safer, and will generally detect the polyps in FAP, since they are numerous and located throughout the colon. Colonoscopy may be the screening tool of choice if attenuated FAP is suspected since, in this case, the adenomas are fewer in number and may be confined to the proximal region of the colon.

If polyposis is established, complete colonoscopy may be necessary to determine the extent of the polyposis and the timing of surgery. As for surgical intervention, total proctocolectomy (removal of the colon and rectum) is generally favored. In some cases, however, other options may be explored, such as total colectomy (removal of the colon only) with ileorectal anastomosis (the small intestine is attached to the upper portion of the rectum). Another option, a total colectomy with rectal mucosal protectomy and ileoanal anastomosis, involves removing the entire colon and mucosal lining of the rectum. The ileum then attaches to the anus. Fecal continence is preserved since the muscular wall and the sensory functions of the rectum are preserved.

All FAP patients require an annual medical examination with palpation of the thyroid and review of systems. Children with FAP should be screened for hepatoblastoma with liver palpation. In some cases, hepatic ultrasonography and determination of serum alpha-fetoprotein levels can be helpful as well. Upper endoscopy (visual examination of the upper GI tract) should be completed every one to four years to evaluate for gastric and duodenal polyps. Duodenal polyps that increase in size or number or show signs of becoming cancerous may require treatment. This treatment may include evaluation by computed tomography or ultrasonography. If necessary, the polyps may be removed by laser or other procedures.

For at-risk relatives of affected individuals, regular screening should begin between the ages of 10 and 12 years. This screening can be accomplished by protein truncation testing. If the test result is a true negative (i.e., negative result in a person whose affected relative had a positive result), further screening is debatable. This test result should theoretically eliminate the risk of FAP but, in very few cases, laboratory errors or other circumstances may lead to an inaccurate test result. Thus, some experts suggest that flexible sigmoidoscopy should be performed at ages 18, 25, and 35 years in these individuals, with standard screening thereafter.

After colectomy, continued surveillance of patients with FAP is advised. Ileoscopy is recommended every

three to five years. This procedure examines the ileum, or lowest third of the small intestine, and serves to rule out polyps, which may become cancerous with time. Surgical removal of desmoid tumors is invasive but often necessary to prevent reoccurrence. Various nonoperative treatments have been attempted, such as medication and radiation, none of which have yielded consistent results. Additionally, the examination of any remaining rectal tissue by proctoscopy is necessary every six months to assess for signs of rectal cancer.

As with any abdominal surgeries in people affected with FAP, there is a risk of developing desmoid tumors after the colectomy. If desmoids are suspected, computed tomography is the recommended imaging study. MRI may also be used in certain cases.

Surveillance of the upper GI tract, even after total proctocoloectomy, is appropriate due to the incidence of tumors in this area previously discussed.

Prognosis

Without colectomy, the prognosis for individuals with FAP is very poor. Patients who have not undergone colectomy develop colorectal cancer at an average age of 39 years. The majority of untreated people die from colorectal cancer by the age of 42 years. For those who do undergo a colectomy, prognosis is variable, depending on development and progression of other tumors. For example, desmoids can also be detrimental to those affected with FAP, accounting for 11–31% of all mortality in these individuals.

Resources

PERIODICALS

King, John E., Roger R. Dozois, Noralane M. Lindor, and David A. Ahlquist. “Care of Patients and Their Families With Familal Adenomatous Polyposis.” Mayo Clinic Proceedings 75, no. 1 (January 2000): 57–67.

Lynch, Henry T., and Thomas C. Smyrk. “Hereditary Colorectal Cancer.” Seminars in Oncology 26, no. 5 (October 1999): 478–484.

Olson, Sharon J., and Kristin Zawacki. “Hereditary Colorectal Cancer.” Clinical Genetics 35, no. 3 (September 2000): 671–685.

ORGANIZATIONS

Colon Cancer Alliance. 175 Ninth Ave. New York, NY 10011. (212) 627-7451. http://ccalliance.org .

Colorectal Cancer Network. PO Box 182, Kensington, MD 20895-0182. (301) 879-1500. http://www.colorectalcancer.net .

Hereditary Colon Cancer Association (HCCA). 3601 N 4th Ave., Suite 201, Sioux Falls, SD 57104. (800) 264-6783.http://hereditarycc.org .

polyposis adenomatous Familial

Familial dysautonomia

WEBSITES

“Familial Adenomatous Polyposis.” Gene Clinics. http://www. geneclinics.org .

Johns Hopkins Medical Institutions. “FAP. Hereditary Colorectal Cancer.” http://www.hopkins-coloncancer

.org/subspecialties/heredicolor_cancer/overview.htm . National Cancer Institute. “Genetics of Colorectal Cancer (PDQ).” CancerNet. http://cancernet.nci.nih.gov .

Mary E. Freivogel, MS

I Familial dysautonomia

Definition

Familial dysautonomia (FD) is a rare inherited disorder in which affected individuals experience multiple malfunctions of the autonomic nervous system (the part of the nervous system that regulates heart muscle, smooth muscle, and glands) as well as the sensory, motor, and central components of the nervous system. The disorder is progressive with a continual loss of nerve cells of the sensory and autonomic nervous systems.

Description

Familial dysautonomia is an inherited disorder that occurs almost exclusively in people of Eastern European (Ashkenazi) Jewish descent. FD is one of a larger group of at least five hereditary sensory and autonomic neuropathies (HSANs), meaning conditions that stem from abnormalities of the nervous system. FD was first described in 1949 by pediatricians Conrad Riley and Richard Day. They reported five children, all Jewish, who had an unusual set of reactions to mild anxiety, attributed to a disturbance of the autonomic nervous system. FD is also known as HSAN type III or Riley-Day syndrome. Decades of studies have determined the cause to be a genetic abnormality that causes poor development of nerve cells in the fetus, leading to a progressive loss of nerve cells of the autonomic and sensory nervous systems. The depletion of nerve cells in the autonomic system causes problems with unstable heart rate, blood pressure, and body temperature, as well as gastrointestinal dysfunction, poor motor coordination, and emotional instability. Abnormal development of the sensory nervous system results in poor perception of pain, heat, and cold. This causes affected individuals to injure themselves without being aware of it. This deterioration of the nervous system worsens throughout life and causes multiple health problems that lead to the death of 50% of those affected by adulthood.

Genetic profile

FD is caused by mutations (genetic errors) in the IKBKAP gene that is found on human chromosome 9, specifically located at region 9q31. The disease is inherited as an autosomal recessive trait. This means that both parents have one copy of the mutant gene but do not have the disease. For these parents, there is a 25% chance with each pregnancy that the child will have the disease.

The IKBKAP gene has two known mutations, which together account for 100% of the Ashkenazi Jewish (AJ) cases of FD. There is also a third mutation causing FD that is rarely seen in the non-AJ population. This mutation’s gene location has not yet been determined.

Demographics

The abnormal gene causing FD is rare in the general population but has a fairly high incidence in the Ashkenazi Jewish population, originating from Eastern Europe. Both males and females are affected. In the atrisk group, one in 30 people is thought to be a carrier of the abnormal gene, with a disease frequency of one in 3,600 live births. Rare non-Jewish individuals affected with FD have been reported.

Signs and symptoms

Sensory and autonomic nervous systems fail to develop properly in the fetus. Newborn babies with FD have poor or decreased muscle tone and have poor sucking and swallowing reflexes that make feeding difficult. Affected babies are prone to periods of abnormally low body temperature and are unable to produce adequate tears when crying.

Although symptoms vary markedly, by adolescence affected children have a 90% likelihood of spinal curvature and experience weakness and leg cramping. They have difficulty concentrating and undergo personality changes including negativism, depression, irritability, and insomnia. Forty percent of affected people have regular vomiting crises in response to either emotional or physical stress. A crisis typically involves one to three days of compulsive vomiting, rapid heart rate, high blood pressure, profuse sweating, and red, blotchy skin.

Between crises, affected individuals may experience low blood pressure when rising to a standing position. They often have unexplained fevers and may have convulsions in response to even mild infections. Uncoordinated swallowing, reflux of stomach contents, and a poor gag reflex result in food or fluids being misdirected into the trachea and lungs. Aspiration pneumonia (lung infections) often follows. Kidney function may deteriorate with age. Affected people have an abnormal

response to low oxygen or high carbon dioxide in their blood. They do not experience the expected “air hunger,” or urge to breathe, and may faint or have a seizure. Lack of tears, decreased blink frequency, and insensitivity of the eye to pain from foreign objects can cause inflammation and ulcers of the cornea.

A characteristic sign in those affected with FD is a lack of the sense of taste. This is due to the absence of taste buds on the tongue. Other sensory problems include an inability to feel pain or distinguish between hot and cold temperatures; sensory loss increases with age. Deep tendon reflexes in affected individuals are decreased. Poor speech and motor coordination result in abnormal gait, unsteadiness, tongue thrusting, and abnormal rhythmic facial movements. Growth is stunted, with an average adult height of 5 ft (1.5 m). Puberty is delayed in both sexes. However, fertility and offspring of affected individuals are normal.

Diagnosis

The presentation of FD varies between affected people. However, of the many manifestations of the disease, five signs are key to the diagnosis:

1.flat, smooth tongue due to lack of taste buds,

2.lack of red flare following histamine injection under the skin,

3.decreased or absent deep tendon reflexes,

4.absence of overflow tears with emotional crying,

5.parents of Ashkenazi Jewish background.

Other frequent signs are decreased response to pain and temperature, decreased corneal reflexes, unstable blood pressure, low blood pressure when standing erect, red blotching of the skin, and increased sweating. Further supportive evidence of the FD diagnosis are feeding difficulties, repeated aspiration pneumonia, episodes of low body temperature, breath holding spells, poor muscle tone, delayed motor development, repeated vomiting, spinal curvature, and poor growth. Prenatal diagnosis, screenings for carrier status, and genetic counseling are available.

Treatment and management

The identification of the FD gene as IKBKAP was reported in March 2001, and is expected to lead to new treatment approaches as the function of the gene is better understood. Until that time, treatment is preventive and supportive. Management of vomiting crises is attempted with drugs, replacement of body fluids, prevention of aspiration of stomach contents into lungs, control of blood pressure, and promotion of sleep. Care of the eyes

K E Y T E R M S

Aspiration pneumonia—Lung infection due to food or liquids accidentally getting into lungs.

Autonomic nervous system—The part of the nervous system that regulates heart muscle, smooth muscle, and glands.

Autosomal—Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes.

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.

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.

Recessive—Genetic trait expressed only when present on both members of a pair of chromosomes, one inherited from each parent.

includes artificial tears, eyewashes, and topical antibiotics to avoid ulcers of the cornea. Early and adequate treatment of even mild infections is important to avoid triggering vomiting crises. Children should be protected from injury and watched for any unusual swellings or skin discolorations as a way of coping with decreased pain and temperature perception.

Physical and occupational therapy, braces, and other orthopedic aids are used for spinal curvature and poor motor coordination. Speech therapy, special feeding techniques, and respiratory care enhance quality of life. It is important to maintain adequate fluid intake and avoid situations such as high elevations, air travel, and diving underwater where oxygen concentration is decreased. Psychological intervention is helpful to alleviate emotional instability and mood swings in children and depression, anxiety, and phobias in adults.

Prognosis

The disease process of familial dysautonomia can not be prevented at present but 80% of affected individuals survive beyond childhood and 50% reach age 30. With the 2001 determination of the exact location of the gene abnormality, prospects for new treatments and possible gene therapy are on the horizon.

dysautonomia Familial

Familial Mediterranean fever

Resources

BOOKS

Gilbert, Patricia. Riley-Day Syndrome. The A-Z Reference Book of Syndromes and Inherited Disorders. 2nd ed. San Diego: Singular Publishing Group, Inc., 1996.

PERIODICALS

Axelrod, Felicia B. “Familial Dysautonomia: A 47-year Perspective.” Journal of Pediatrics 132, no.3 (March 1998): S2-5.

Gelbart, Marsh. “In Our Parents’ Shadow. Riley-Day Syndrome.” Nursing Times 95, no. 6 (February 10-16, 1999): 33.

ORGANIZATIONS

Dysautonomia Foundation, Inc. 633 Third Ave., 12th Floor, New York, NY 10017-6706. (212) 949-6644. www.med

.nyu.edu/fd/fdcenter.html .

Marianne O’Connor, MT (ASCP), MPH

Familial endocrine adenomatosis see

Multiple endocrine neoplasia

Familial fatal insomnia see Prion diseases

Familial infiltrative fibromatosis see

Hereditary desmoid disease

I Familial Mediterranean fever

Definition

Familial Mediterranean fever (FMF) is an inherited disorder of the inflammatory response characterized by recurring attacks of fever, accompanied by intense pain in the abdomen, chest, or joints. Attacks usually last 12–72 hours, and can occasionally involve a skin rash. Kidney disease is a serious concern if the disorder is not treated. FMF is most prevalent in people of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry.

Description

FMF could be described as a disorder of “inappropriate” inflammation. That is, an event that in a normal situation causes a mild or unnoticeable inflammation might cause a severe inflammatory response in someone with FMF. Certain areas of the body are at risk for FMFrelated symptoms. A serosa is a serous (fluid-producing) membrane that can be found inside the abdominal cavity (peritoneum), around the lungs (pleura), around the heart (pericardium), and inside the joints (synovium). The

symptoms of FMF are due to inflammation of one or more of the serosal membranes (serositis). Thus, FMF is also sometimes called recurrent polyserositis.

During an attack, large numbers of neutrophils, a type of white blood cell, move into the affected areas causing painful inflammation and fever. These episodes may be accompanied by a skin rash or joint pain. In a few cases, chronic arthritis is a problem. Amyloidosis is a potentially serious condition in which proteins called amyloids are mistakenly produced and deposited in organs and tissues throughout the body. Left untreated, amyloidosis often leads to kidney failure, which is the major long-term health risk in FMF.

In most cases, the attacks of fever and pain are first noticed in childhood or adolescence. The interval between these episodes may be days or months, and is not predictable. However, during these intervals people with FMF typically lead normal lives. It is not entirely clear what brings on an attack, but people with FMF often report mild physical trauma, physical exertion, or emotional stress just prior to the onset of symptoms. Treatment for FMF involves an oral medication called colchicine, which is highly effective for the episodes of fever and pain, as well as for amyloidosis and the kidney disease that can result from it.

FMF is most common in certain ethnic groups from the eastern Mediterranean region, but cases in other ethnic groups in other parts of the world are increasingly being reported. FMF is also known by many other names. They include: recurrent hereditary polyserositis, benign paroxysmal peritonitis, familial paroxysmal polyserositis, paroxysmal polyserositis, familial recurrent polyserositis, periodic fever, periodic amyloid syndrome, periodic peritonitis syndrome, Reimann periodic disease, Reimann syndrome, Siegel-Cattan-Mamou syndrome, and Armenian syndrome.

Genetic profile

FMF is a genetic condition inherited in an autosomal recessive fashion. Mutations in the MEFV gene (short for Mediterranean Fever) on chromosome number 16 are the underlying cause of FMF. Autosomal recessive inheritance implies that a person with FMF has mutations in both copies of the MEFV gene. All genes come in pairs, and one copy of each pair is inherited from each parent. If neither parent of a child with FMF has the condition, it means they carry one mutated copy of the MEFV gene, but also one normal copy, which is enough to protect them from disease. If both parents carry the same autosomal recessive gene, there is a one in four chance in each pregnancy that the child will inherit both recessive genes, and thus have the condition.