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

The MEFV gene carries the instructions for production of a protein called pyrin, named for pyrexia, a medical term for fever. The research group in France that co-discovered the protein named it marenostrin, after ancient Latin words that referred to the Mediterranean Sea. The movement of neutrophils into an area of the body where trauma or infection has occurred is the major cause of inflammation, which is a normal process. Research has shown that pyrin has some function in controlling neutrophils. In a situation where minor trauma or stress occurs, some initial inflammation may follow, but a functional pyrin protein is responsible for shuttingdown the response of neutrophils once they are no longer needed. An abnormal pyrin protein associated with FMF may be partly functional, but unstable. In some instances, the abnormal pyrin itself seems to be “stressed,” and loses its ability to regulate neutrophils and inflammation. Left unregulated, a normal, mild inflammation spirals out of control. Exactly what causes pyrin in FMF to lose its ability to control neutrophils in some situations is not known.

Demographics

Estimates of the incidence of FMF in specific eastern Mediterranean populations range from one in 2,000 to one in 100, depending on the population studied. Specific mutations in the MEFV gene are more common in certain ethnic groups, and may cause a somewhat different course of the disease. A few mutations in the MEFV gene likely became common in a small population in the eastern Mediterranean several thousand years ago. It is postulated that carrying a single copy of a mutated gene produced a modified (but not abnormal) inflammatory response that may have been protective against some infectious agent at that time. Those who carried a single “beneficial” mutation in the MEFV gene were more likely to survive and reproduce, which may explain the high carrier frequency (up to one in five) in some populations. People of Armenian, SephardicJewish, Arabic, and Turkish ancestry are at greatest risk for FMF. However, a better understanding and recognition of the symptoms of FMF in recent years has resulted in more reports of the condition in other ethnic groups, such as Italians and Armenian-Americans.

Signs and symptoms

The recurrent acute attacks of FMF typically begin in childhood or adolescence. Episodes of fever and painful inflammation usually last 12–72 hours. About 90% of people with FMF have their first attack by age 20. The group of symptoms that characterizes FMF includes the following:

K E Y T E R M S

Acute phase reactants—Blood proteins whose concentrations increase or decrease in reaction to the inflammation process.

Amyloid—A waxy translucent substance, composed mostly of protein, that forms plaques (abnormal deposits) in the brain.

Amyloidosis—Accumulation of amyloid deposits in various organs and tissues in the body such that normal functioning of an organ is compromised.

Colchicine—A compound that blocks the assembly of microtubules—protein fibers necessary for cell division and some kinds of cell movements, including neutrophil migration. Side effects may include diarrhea, abdominal bloating, and gas.

Leukocyte—A white blood cell. The neutrophils are a type of leukocyte.

Leukocytosis—An increase in the number of leukocytes in the blood.

Neutrophil—The primary type of white blood cell involved in inflammation. Neutrophils are a type of granulocyte, also known as a polymorphonuclear leukocyte.

Pericarditis—Inflammation of the pericardium, the membrane surrounding the heart.

Peritonitis—Inflammation of the peritoneum, the membrane surrounding the abdominal contents.

Pleuritis—Inflammation of the pleura, the membrane surrounding the lungs.

Pyrexia—A medical term denoting fevers.

Serositis—Inflammation of a serosal membrane. Polyserositis refers to the inflammation of two or more serosal membranes.

Synovitis—Inflammation of the synovium, a membrane found inside joints.

Fever

An FMF attack is nearly always accompanied by a fever, but it may not be noticed in every case. Fevers are typically 100–104°F (38–40°C). Some people experience chills prior to the onset of fever.

Abdominal pain

Nearly all people with FMF experience abdominal pain at one point or another, and for most it is the most common complaint. The pain can range from mild to

fever Mediterranean Familial

Familial Mediterranean fever

severe, and can be diffuse or localized. It can mimic appendicitis, and many people with undiagnosed FMF have had appendectomies or exploratory surgery of the abdomen done, only to have the fever and abdominal pain return.

Chest pain

Pleuritis, also called pleurisy, occurs in up to half of the affected individuals in certain ethnic groups. The pain is usually on one side of the chest. Pericarditis would also be felt as chest pain.

Joint pain

About 50% of people with FMF experience joint pain during attacks. The pain is usually confined to one joint at a time, and often involves the hip, knee, or ankle. For some people, however, the recurrent joint pain becomes chronic arthritis.

Myalgia

Up to 20% of individuals report muscle pain. These episodes typically last less than two days, and tend to occur in the evening or after physical exertion. Rare cases of muscle pain and fever lasting up to one month have been reported.

Skin rash

A rash, described as erysipelas-like erythema, accompanies attacks in a minority of people, and most often occurs on the front of the lower leg or top of the foot. The rash appears as a red, warm, swollen area about 4–6 in (10–15 cm) in diameter.

Amyloidosis

FMF is associated with high levels in the blood of a protein called serum amyloid A (SAA). Over time, excess SAA tends to be deposited in tissues and organs throughout the body. The presence and deposition of excess SAA is known as amyloidosis. Amyloidosis may affect the gastrointestinal tract, liver, spleen, heart, and testes, but effects on the kidneys are of greatest concern. The frequency of amyloidosis varies among the different ethnic groups, and its overall incidence is difficult to determine because of the use of colchicine to avert the problem. Left untreated, however, those individuals who do develop amyloidosis of the kidneys may require a renal transplant, or may even die of renal failure. The frequency and severity of a person’s attacks of fever and serositis seem to have no relation to whether they will develop amyloidosis. In fact, a few people with FMF have been described who have had amyloidosis but apparently no other FMF-related symptoms.

Other symptoms

A small percentage of boys with FMF develop painful inflammation around the testes. Headaches are a common occurrence during attacks, and certain types of vasculitis (inflammation of the blood vessels) seem to be more common in FMF.

Diagnosis

Individually, the symptoms that define FMF are common. Fevers occur for many reasons, and nonspecific pains in the abdomen, chest, and joints are also frequent ailments. Several infections can result in symptoms similar to FMF (Mallaret meningitis, for instance), and many people with FMF undergo exploratory abdominal surgery and ineffective treatments before they are finally diagnosed. Membership in a less commonly affected ethnic group may delay or hinder the correct diagnosis.

In general, symptoms involving one or more of the following broad groups should lead to suspicion of FMF: Unexplained recurrent fevers, polyserositis, skin rash, and/or joint pain; abnormal blood studies (see below); and renal or other disease associated with amyloidosis. A family history of FMF or its symptoms would obviously be an important clue, but the recessive nature of FMF means there usually is no family history. The diagnosis may be confirmed when a person with unexplained fever and pain responds to treatment with colchicine since colchicine is not known to have a beneficial effect on any other condition similar to FMF. Abnormal results on a blood test typically include leukocytosis (elevated number of neutrophils in the blood), an increased erythrocyte sedimentation rate (rate at which red blood cells form a sediment in a blood sample), and increased levels of proteins associated with inflammation (called acute phase reactants) such as SAA.

Direct analysis of the MEFV gene for FMF mutations is the only method to be certain of the diagnosis. However, it is not yet possible to detect all MEFV gene mutations that might cause FMF. Thus, if DNA analysis is negative, clinical methods must be relied upon. If both members of a couple were proven to be FMF carriers through genetic testing, highly accurate prenatal diagnosis would be available in any subsequent pregnancy.

Similar syndromes of periodic fever and inflammation include familial Hibernian fever and hyperimmunoglobulinemia D syndrome, but both are more rare than FMF.

Treatment and management

Colchicine is a chemical compound that can be used as a medication, and is frequently prescribed for gout. Some

years ago, colchicine was discovered to also be effective in reducing the frequency and severity of attacks in FMF. Treatment for FMF at this point consists of taking colchicine daily. Studies have shown that about 75% of FMF patients achieve complete remission of their symptoms, and about 95% show marked improvement when taking colchicine. Lower effectiveness has been reported, but there is some question about the number of FMF patients who choose not to take their colchicine between attacks when they are feeling well, and thus lose some of the ability to prevent attacks. Compliance with taking colchicine every day may be hampered by its side effects, which include diarrhea, nausea, abdominal bloating, and gas. There is a theoretical risk that colchicine use could damage chromosomes in sperms and eggs, or in an embryo during pregnancy, or that it might reduce fertility. However, studies looking at reproduction in men and women who have used colchicine have so far not shown any increased risks. Colchicine is also effective in preventing, delaying, or reversing renal disease associated with amyloidosis.

Other medications may be used as needed to deal with the pain and fever associated with FMF attacks. Dialysis and/or renal transplant might become necessary in someone with advanced kidney disease. Given its genetic nature, there is no cure for FMF, nor is there likely to be in the near future. Any couple that has a child diagnosed with FMF, or anyone with a family history of the condition (especially those in high-risk ethnic groups), should be offered genetic counseling to obtain the most up-to-date information on FMF and testing options.

Prognosis

For those individuals who are diagnosed early enough and take colchicine consistently, the prognosis is excellent. Most will have very few, if any, attacks of fever and polyserositis, and will likely not develop serious complications of amyloidosis. The problem of misdiagnosing FMF continues, but education attempts directed at both the public and medical care providers should improve the situation. Future research should provide a better understanding of the inflammation process, focusing on how neutrophils are genetically regulated. That information could then be used to develop treatments for FMF with fewer side effects, and might also assist in developing therapies for other diseases in which abnormal inflammation and immune response are a problem.

Resources

BOOKS

Kastner, Daniel L. “Intermittent and Periodic Arthritic Syndromes.” Arthritis and Allied Conditions: A Textbook of Rheumatology, edited by William J. Koopman. 13th ed. Baltimore: Williams & Wilkins, 1996.

Sha’ar, Khuzama H., and Haroutone K. Armenian. “Familial Paroxysmal Polyserositis (Familial Mediterranean Fever).” In Genetic Disorders Among Arab Populations, edited by Ahmad S. Teebi, and Talaat I. Faraq. New York: Oxford University Press, 1997.

PERIODICALS

Ben-Chetrit, Eldad, and Micha Levy. “Familial Mediterranean Fever.” The Lancet 351 (February 28, 1998): 659-64.

Kastner, Daniel L. “Familial Mediterranean Fever: The Genetics of Inflammation.” Hospital Practice 33 (April 15, 1998):131-146.

Samuels, Jonathan, et al. “Familial Mediterranean Fever at the Millennium: Clinical Spectrum, Ancient Mutations, and a Survey of 100 American referrals to the National Institutes of Health.” Medicine 77 (July 1998):268-97.

ORGANIZATIONS

National Institute of Arthritis and Musculoskeletal and Skin Diseases. National Institutes of Health, One AMS Circle, Bethesda, MD 20892. http://www.nih.gov/niams .

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 .

National Society of Genetic Counselors. 233 Canterbury Dr., Wallingford, PA 19086-6617. (610) 872-1192. http://www

.nsgc.org/GeneticCounselingYou.asp .

Scott J. Polzin, MS, CGC

Familial polyposis coli (FPC) see Familial adenomatous polyposis

Familial somatotrophinoma see

Acromegaly

Familial spastic parapelegia see Hereditary spastic paraplegia

I Fanconi anemia

Definition

Fanconi anemia is an inherited disorder characterized by a severe form of anemia and various other physical malformations. Patients with Fanconi anemia are susceptible to various types of cancer.

Description

Fanconi anemia (FA) was first described in 1927 by a Swiss pediatrician named Guido Fanconi. It is a rare, inherited form of aplastic anemia. Aplastic anemia is a

anemia Fanconi

Fanconi anemia

K E Y T E R M S

Androgens—A group of steroid hormones that stimulate the development of male sex organs and male secondary sex characteristics.

Anemia—A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values. Common symptoms include paleness, fatigue, and shortness of breath.

Aplastic anemia—A form of anemia characterized by a greatly decreased formation of red and white blood cells as a result of abnormal bone marrow.

Hematopoetic growth factors—Substances that assist in the formation of blood cells.

Hyperpigmentation—An abnormal condition characterized by an excess of melanin in localized areas of the skin, which produces areas that are much darker than the surrounding unaffected skin.

Leukemia—Cancer of the blood forming organs which results in an overproduction of white blood cells.

Platelets—Small disc-shaped structures that circulate in the blood stream and participate in blood clotting.

Red blood cells—Hemoglobin-containing blood cells that transport oxygen from the lungs to tissues. In the tissues, the red blood cells exchange their oxygen for carbon dioxide, which is brought back to the lungs to be exhaled.

White blood cell—A cell in the blood that helps fight infections.

life-threatening condition in which a person is unable to produce adequate amounts of red blood cells, white blood cells, or platelets. Red blood cells serve to carry oxygen to all areas of the body. White blood cells help to fight infection and disease. Platelets are responsible for clotting to help to heal wounds and control bleeding. Without adequate amounts of these important blood cells, patients affected with aplastic anemia are easily fatigued and susceptible to infections. Most cases of aplastic anemia develop throughout the course of a person’s lifetime. However, in FA, the aplastic anemia is inherited, or present from birth.

FA is also associated with various other findings. These include short stature, skeletal abnormalities, kidney problems, and heart defects. Additionally, people with FA experience a high incidence of leukemia and an increased incidence of other types of cancer.

The chromosomes in the cells of FA patients break and rearrange easily. Chromosomes are the information manuals of our cells. Genes are arranged on chromosomes in a linear fashion, like beads are arranged on a string. Genes tell our cells how to make proteins. These proteins perform many vital functions in the body. When chromosomes break, genes are disrupted and they do not function correctly. This leads to abnormal proteins and various health problems. The chromosome breakage in FA can be seen in the laboratory and is used to diagnose the disorder.

Genetic profile

It has been determined that there are at least eight different genes associated with FA. A change in any one of these genes causes the disorder. As of 2001, the proteins made by these genes are not yet known and their role in FA is not yet understood.

For someone to be affected with FA, each of their parents must have a defect in the same gene. Parents that carry the defective gene do not show symptoms of FA because they have a corresponding gene on the other chromosome that produces an adequate amount of protein. Thus, they often do not know they are carriers until they have an affected child. If both parents carry the same defective gene, each pregnancy has a 25% chance of inheriting both abnormal genes and being affected with FA. Likewise, each pregnancy has a 25% chance of inheriting two functional copies of the gene and being unaffected. This leaves a 50% chance that the pregnancy will have one functional gene and one defective gene and will be an unaffected carrier of the disorder. This pattern is known as autosomal recessive inheritance.

The FA genes are designated by a letter of the alphabet. Defects in the FA-A gene account for approximately 65% of FA cases. Defects in the FA-C gene account for about 15% of FA cases. In the Ashkenazi Jewish population, however, defects in this particular gene are responsible for nearly all cases of FA.

Demographics

FA occurs equally in males and females. The total number of FA patients has not been documented. It has been estimated, however, that between one in 100 and one in 600 people carry one of the defective genes. FA is found in all ethnic groups but is more frequent in the Ashkenazi Jewish population. One in every 89 people in this population carry a mutation in the FA-C gene.

Signs and symptoms

The signs and symptoms of FA generally appear between the ages of three and 12. In rare cases, symptoms

anemia Fanconi

Fanconi-Bickel syndrome

This particular test can be completed prenatally if a family desires to know whether or not a child is affected before he or she is born. Cells obtained from the mother’s placenta or cells floating in the amniotic fluid that surrounds the fetus in the womb can be used to detect chromosome breakage.

For families who have a defect in the FA-C gene, it is possible to look directly at the gene to determine whether or not a defect is present. This can detect those who carry the gene defect as well as those who are affected. Carrier testing is offered routinely to those in the Ashkenazi Jewish population since the frequency of carriers is so high.

Treatment and management

Once the diagnosis of FA has been made, several initial tests should be completed, including liver and kidney function studies, a formal hearing evaluation, a developmental assessment, and an ultrasound examination of the kidneys and urinary system.

People affected with FA should be followed closely by a physician. Their blood cell and platelet counts should be monitored frequently. Symptoms caused by anemia and low platelets, such as bleeding, fatigue, chest pain, and dizziness, can be treated with transfusions as needed. Antibiotics are often given to fight infections. At times, hospitalization may be necessary to adequately tend to these complications. As patients get older, they should be monitored for any signs of solid tumor cancers.

Due to either aplastic anemia or leukemia, many individuals with FA will eventually require a bone marrow transplant. The donor must be carefully matched to the patient. The prognosis for transplant is best for young patients who have an sibling donor with a matching tissue type.

Between 50 and 75% of individuals with FA will respond to androgens. These are artificial male hormones that can stimulate production of one or more types of blood cells. They are most effective in increasing the number of red blood cells but can increase platelets and white cells as well. These drugs prolong the lives of individuals with FA but are not a cure.

As of 2001, various hematopoetic growth factors have been studied in relation to FA. These substances are already present in the body and serve to stimulate the production of blood cells and platelets. Scientists have developed a way to manufacture these substances. They have been given to patients with FA and show promise in increasing the counts of blood cells and platelets.

Prognosis

FA is an unpredictable illness. The average life expectancy for an affected individual is 22 years, but any one individual can have a lifespan that is quite different from this average. Research discoveries have led to lifeextending treatments and improved bone marrow transplant outcome. However, as patients live longer, they become at an increased risk to develop other types of tumors.

Resources

BOOKS

Frohnmayer, Lynn and Dave. Fanconi Anemia: A Handbook for Families and Their Physicians. Fanconi Anemia Research Fund, Inc., 2000.

PERIODICALS

Auerbach, A.D. “Fanconi Anemia.” Dermatologic Clinics 13 (January 1995): 41-49.

ORGANIZATIONS

Aplastic Anemia Foundation. PO Box 613, Annapolis, MD 21404-0613. (800) 747-2820. http://www.aplastic.org .

Fanconi Anemia Research Fund. 1801 Willamette St., Suite 200, Eugene, OR 97401-4030. (800) 828-4891.http://www.fanconi.org .

Leukaemia Research Fund. 43 Great Ormond St., London, WC1N 3JJ. 020-7405-3139. http://dspace.dial.pipex

.com/lrf .

WEBSITES

“Fanconi Anemia.” Leukaemia Research Fund. http://dspace

.dial.pipex.com/lrf-/diseases/fanconi_book.htm .

Fanconi Anemia Research Fund. http://www.fanconi.org .

Mary E. Freivogel, MS

I Fanconi-Bickel syndrome

Definition

Fanconi-Bickel syndrome (FBS) is a rare inherited disorder of carbohydrate metabolism caused by mutations in the gene known as GLUT2.

Description

Also known as glycogen storage disease type XI, the disease was first described by scientists G. Fanconi and Horst Bickel in 1949. Since then, only a few dozen cases of FBS have been studied, most in the United States, Europe, and Japan.

Onset of FBS is within the first year of life, with the overt symptom being a failure to thrive. At age two, an

enlarged liver and kidneys are present and the child has rickets. The incidence of FBS has not been determined but it is believed to occur in less than one in one million births.

Genetic profile

FBS is believed to be an autosomal recessive disorder. This means that an individual with FBS would have to inherit an abnormal copy of the gene from both parents in order to show symptoms of FBS. People with only one abnormal gene are carriers and do not have the disorder. When both parents have the abnormal gene, there is a 25% chance with each birth that their child will inherit both abnormal genes and have the disease. There is a 50% chance each birth that the 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. The specific genetic defect of FBS has not been identified.

Demographics

Since there is so little research on Fanconi-Bickel syndrome, no clear pattern of demographics has been established. However, the disorder is known to affect both males and females. One common thread in some of the cases that have been studied has been consanguinity, meaning that FBS is found in the children of two persons of the same blood relation. In several of these cases the consanguinity is between two first cousins.

Signs and symptoms

In a 1987 study by researchers at the Research Institute for Child Nutrition in Dortmund, Germany, nine cases of Fanconi-Bickel syndrome were compared for clinical symptoms, behavior symptoms, and physical appearance. The initial symptoms reported were fever, vomiting, growth failure, and rickets between the ages of three and ten months. Later, these same patients showed signs of dwarfism, a protruding abdomen, enlarged liver, moon-shaped face, and abnormal fat deposits around the shoulders and abdomen. Also, cutting of teeth and puberty were delayed. Complications present included fractures and pancreatitis (an enlarged pancreas). Later in life, rickets and osteoporosis were constant features.

The German study, whose researchers included H. Bickel, co-discoverer of the syndrome, also used ultrasound to determine increased kidney size and growth in relation to body height. The most prominent finding was glucosuria (glucose, or sugar, in the urine). Polyuria (increased urination) was also a constant finding. The

K E Y T E R M S

Carbohydrate—Any of various natural compounds of carbon, hydrogen, and oxygen (as in sugars and starches) that are burned by the body for energy.

Diabetes mellitus—The clinical name for common diabetes. It is a chronic disease characterized by inadequate production or use of insulin.

Hyperlordosis—An exaggerated curve in the lower (lumbar) portion of the back.

Osteoporosis—Loss of bone density that can increase the risk of fractures.

Pancreas—An organ located in the abdomen that secretes pancreatic juices for digestion and hormones for maintaining blood sugar levels.

Pancreatitis—Inflammation of the pancreas.

Rickets—A childhood disease caused by vitamin D deficiency, resulting in soft and malformed bones.

study noted that liver size was normal or slightly increased at birth in all nine cases but became greatly enlarged during infancy. The liver size and glycogen (a glucose storage molecule) content were reduced when the patients were placed on an antiketogenic (high carbohydrate) diet.

Other laboratory findings included fasting hypoglycemia (low levels of sugar in the blood), ketonuria (high levels of ketones in the urine), high hypercholesterolemia (high cholesterol), hypophosphatemia (high phosphate levels in the blood), and high levels of amino acids and protein in the urine. In a 1995 study at Children’s Hospital in Philadelphia of an eight-year-old with Fanconi-Bickel syndrome, doctors reported additional symptoms of overworked kidneys, very small amounts of albumin (a class of water soluble proteins) in the urine, and an increase in the number of cells in the inner part of the kidney that filters blood.

Diagnosis

Fanconi-Bickel syndrome can usually be identified in patients by neonatal screening for galactose, a type of sugar. Patients with FBS are intolerant to galactose. Other diagnostic factors include an impaired glucose tolerance test, x ray to determine the pattern of rickets, urine tests to measure levels of glycose, phosphates, amino acids, and bicarbonate, and a liver biopsy to detect abnormal galactose oxidation.

syndrome Bickel-Fanconi

Fetal alcohol syndrome

Treatment and management

There is no effective treatment for Fanconi-Bickel syndrome. However, some of the symptoms can be treated with adequate supplementation of water, electrolytes, and vitamin D, restriction of galactose, and a diabetes mellitus-like diet (low sugar and low carbohydrate) presented in frequent small meals. These treatments can improve growth and give the patient a general sense of well-being.

Prognosis

The long-term prognosis has not been determined. It may depend on the severity of symptoms and early diagnosis and treatment of symptoms. The first person diagnosed with the disorder in 1949 was a four-year-old Swiss boy with consanguineous parents. At six months, the boy had excessive thirst, constipation, and was not thriving. He was treated with vitamin D and calcium supplements. At about age four, the boy had short stature, a protruding abdomen, an enlarged liver, facial obesity, osteopenia, and hyperlordosis. At age 12, the boy was found to be resistant to glycogen. In 1997 at age 52, the patient, without any treatment other than vitamin D and calcium supplements, was of short stature (4 ft 8 in or 140 cm tall), weighed about 95 lbs (43 kg), had a moderately protruding abdomen, and a smaller than normal liver. Other than arthritis, he had no medical complaints. However, other people diagnosed as children with FBS had much shorter life spans. Long-term fol- low-up studies of nine persons with FBS showed severely retarded growth, partly compensated for by late onset of puberty.

Resources

PERIODICALS

Manz, F., et al. “Fanconi-Bickel Syndrome.” Pediatric Nephrology (July 1987): 509-518.

Muller, D., et al. “Fanconi-Bickel Syndrome Presenting in Neonatal Screening for Galactosaemia.” Journal of Inherited Metabolic Disease (August 1997): 20-24.

Sahin, Figen, et al. “Glycogen Storage Disease with Renal Tubular Dysfunction (Type XI, Fanconi-Bickel Syndrome).” Archives of Pediatrics and Adolescent Medicine

(November 2000): 1165.

ORGANIZATIONS

American Association of Kidney Patients. 100 S. Ashley Dr., Suite 280, Tampa, FL 33602. (800) 749-2257.http://www.aakp.org .

National Kidney Foundation. 30 East 33rd St., New York, NY 10016. (800) 622-9010. http://www.kidney.org .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812. (203) 746-6518 or (800) 9996673. Fax: (203) 746-6481. http://www.rarediseases.org .

WEBSITES

“Fanconi-Bickel Syndrome; FBS.” (Entry No. 227810). National Center for Biotechnology Information, Online Mendelian Inheritance in Man (OMIM). http://www3

.ncbi.nlm.nih.gov/ .

Ken R. Wells

Fatty aldehyde dehydrogenase deficiency (FALDH10 deficiency) see Sjögren

Larsson syndrome

Feingold syndrome see Oculo-digito- esophago-duodenal syndrome

I Fetal alcohol syndrome

Definition

Fetal alcohol syndrome (FAS) is a pattern of birth defects, learning, and behavioral problems affecting individuals whose mothers consumed alcohol during pregnancy.

Description

FAS is the most common preventable cause of mental retardation. This condition was first recognized and reported in the medical literature in 1968 in France and in 1973 in the United States. Alcohol is a teratogen, the term used for any drug, chemical, maternal disease or other environmental exposure that can cause birth defects or functional impairment in a developing fetus. Some features may be present at birth including low birth weight, prematurity, and microcephaly. Characteristic facial features may be present at birth, or may become more obvious over time. Signs of brain damage include delays in development, behavioral abnormalities, and mental retardation, but affected individuals exhibit a wide range of abilities and disabilities. It has only been since 1991 that the long-term outcome of FAS has been known. Learning, behavioral, and emotional problems are common in adolescents and adults with FAS. Fetal alcohol effect (FAE), a term no longer favored, is sometimes used to describe individuals with some, but not all, of the features of FAS. In 1996, the Institute of Medicine suggested a five-level system to describe the birth defects, learning and behavioral difficulties in offspring of women who drank alcohol during pregnancy. This system contains criteria including confirmation of maternal alcohol exposure, characteristic facial features, growth problems, learning and behavioral problems, and birth

defects known to be associated with prenatal alcohol exposure.

The incidence of FAS varies among different populations studied, and ranges from approximately one in 200 to one in 2000 at birth. However, a recent study reported in 1997, utilizing the Institute of Medicine criteria, estimated the prevalence in Seattle, Washington from 1975–1981 at nearly one in 100 live births. Avoiding alcohol during pregnancy, including the earliest weeks of the pregnancy, can prevent FAS. There is no amount of alcohol use during pregnancy that has been proven to be completely safe.

Genetic profile

FAS is not a genetic or inherited disorder. It is a pattern of birth defects, learning, and behavioral problems that are the result of maternal alcohol use during the pregnancy. The alcohol freely crosses the placenta and causes damage to the developing embryo or fetus. Alcohol use by the father cannot cause FAS. If a woman who has FAS drinks alcohol during pregnancy, then she may also have a child with FAS. Not all individuals from alcohol exposed pregnancies have obvious signs or symptoms of FAS; individuals of different genetic backgrounds may be more or less susceptible to the damage that alcohol can cause. The dose of alcohol, the time during pregnancy that alcohol is used, and the pattern of alcohol use all contribute to the different signs and symptoms that are found.

Demographics

There is no racial or ethnic predilection for FAS. Individuals from different genetic backgrounds exposed to similar amounts of alcohol during pregnancy may exhibit different signs or symptoms of FAS. Several studies have estimated that 25-45% of chronic alcoholic women will give birth to a child with FAS if they continue to drink during pregnancy. The risk of FAS appears to increase as a chronic alcoholic woman progresses in her childbearing years and continues to drink. That is, a child with FAS will often be one of the last born to a chronic alcoholic woman, although older siblings may exhibit milder features of FAS. Binge drinking, defined as sporadic use of five or more standard alcoholic drinks per occasion, and “moderate” daily drinking (two to four 12 oz bottles of beer, eight to 16 ounces of wine, two to four ounces of liquor) can also result in offspring with features of FAS.

Signs and symptoms

Classic features of FAS include short stature, low birthweight and poor weight gain, microcephaly, and a

K E Y T E R M S

Cleft palate—A congenital malformation in which there is an abnormal opening in the roof of the mouth that allows the nasal passages and the mouth to be improperly connected.

Congenital—Refers to a disorder which is present at birth.

IQ—Abbreviation for Intelligence Quotient. Compares an individual’s mental age to his/her true or chronological age and multiplies that ratio by 100.

Microcephaly—An abnormally small head.

Miscarriage—Spontaneous pregnancy loss.

Placenta—The organ responsible for oxygen and nutrition exchange between a pregnant mother and her developing baby.

Strabismus—An improper muscle balance of the ocular musles resulting in crossed or divergent eyes.

Teratogen—Any drug, chemical, maternal disease, or exposure that can cause physical or functional defects in an exposed embryo or fetus.

characteristic pattern of facial features. These facial features in infants and children may include small eye openings (measured from inner corner to outer corner), epicanthal folds (folds of tissue at the inner corner of the eye), small or short nose, low or flat nasal bridge, smooth or poorly developed philtrum (the area of the upper lip above the colored part of the lip and below the nose), thin upper lip, and small chin. Some of these features are nonspecific, meaning they can occur in other conditions, or be appropriate for age, racial, or family background. Other major and minor birth defects that have been reported include cleft palate, congenital heart defects, strabismus, hearing loss, defects of the spine and joints, alteration of the hand creases and small fingernails and toenails. Since FAS was first described in infants and children, the diagnosis is sometimes more difficult to recognize in older adolescents and adults. Short stature and microcephaly remain common features, but weight may normalize, and the individual may actually become overweight for his/her height. The chin and nose grow proportionately more than the middle part of the face and dental crowding may become a problem. The small eye openings and the appearance of the upper lip and philtrum may continue to be characteristic. Pubertal changes typically occur at the normal time.

syndrome alcohol Fetal

Fetal alcohol syndrome

Newborns with FAS may have difficulties with feeding due to sucking difficulties, have irregular sleep-wake cycles, decreased or increased muscle tone, or seizures or tremors. Delays in achieving developmental milestones such as rolling over, crawling, walking, and talking may become apparent in infancy. Behavior and learning difficulties typical in the preschool or early school years include poor attention span, hyperactivity, poor motor skills, and slow language development. Attention deficithyperactivity disorder is a common associated diagnosis. Learning disabilities or mental retardation may be diagnosed during this time. Arithmetic is often the most difficult subject for a child with FAS. During middle school and high school years the behavioral difficulties and learning difficulties can be significant. Memory problems, poor judgment, difficulties with daily living skills, difficulties with abstract reasoning skills, and poor social skills are often apparent by this time. It is important to note that animal and human studies have shown that neurologic and behavioral abnormalities can be present without characteristic facial features. These individuals may not be identified as having FAS, but may fulfill criteria for alcohol related diagnoses, as set forth by the Institute of Medicine.

In 1991, Streissguth and others reported some of the first long-term follow-up studies of adolescents and adults with FAS. In the approximately 60 individuals they studied, the average IQ was 68, with 70 being the lower limit of the normal range. However, the range of IQ was quite large, as low as 20 (severely retarded) to as high as 105 (normal). The average achievement levels for reading, spelling, and arithmetic were fourth grade, third grade and second grade, respectively. The Vineland Adaptive Behavior Scale was used to measure adaptive functioning in these individuals. The composite score for this group showed functioning at the level of a seven- year-old. Daily living skills were at a level of nine years, and social skills were at the level of a six-year-old.

In 1996, Streissguth and others published further data regarding the disabilities in children, adolescents, and adults with FAS. Secondary disabilities, that is, those disabilities not present at birth and that might be preventable with proper diagnosis, treatment, and intervention, were described. These secondary disabilities include: mental health problems; disrupted school experiences; trouble with the law; incarceration for mental health problems, drug abuse, or a crime; inappropriate sexual behavior; alcohol and drug abuse; problems with employment; dependent living; and difficulties parenting their own children. In that study, only seven out of 90 adults were living and working independently and successfully. In addition to the studies by Streissguth, several other authors in different countries have now

reported on long term outcome of individuals diagnosed with FAS. In general, the neurologic, behavioral, and emotional disorders become the most problematic for the individuals. The physical features change over time, sometimes making the correct diagnosis more difficult in older individuals, without old photographs and other historical data to review. Mental health problems including attention deficit, depression, panic attacks, psychosis, and suicide threats and attempts were present in over 90% of the individuals studied by Streissguth. A 1996 study in Germany reported more than 70% of the adolescents they studied had persistent and severe developmental disabilities and many had psychiatric disorders, the most common of which were emotional disorders, repetitive habits, speech disorders, and hyperactivity disorders.

Diagnosis

FAS is a clinical diagnosis, which means that there is no blood, x ray, or psychological test that can be performed to confirm the suspected diagnosis. The diagnosis is made based on the history of maternal alcohol use, and detailed physical examination for the characteristic major and minor birth defects and characteristic facial features. It is often helpful to examine siblings and parents of an individual suspected of having FAS, either in person or by photographs, to determine whether findings on the examination might be familial, of if other siblings may also be affected. Sometimes, genetic tests are performed to rule out other conditions that may present with developmental delay or birth defects. Individuals with developmental delay, birth defects, or other unusual features are often referred to a clinical geneticist, developmental pediatrician, or neurologist for evaluation and diagnosis of FAS. Psychoeducational testing to determine IQ and/or the presence of learning disabilities may also be part of the evaluation process.

Treatment and management

There is no treatment for FAS that will reverse or change the physical features or brain damage associated with maternal alcohol use during the pregnancy. Most of the birth defects associated with prenatal alcohol exposure are correctable with surgery. Children should have psychoeducational evaluation to help plan appropriate educational interventions. Common associated diagnoses such as attention deficit-hyperactivity disorder, depression, or anxiety should be recognized and treated appropriately. The disabilities that present during childhood persist into adult life. However, some of the secondary disabilities mentioned above may be avoided or lessened by early and correct diagnosis, better understanding of