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

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Beckwith-Wiedemann syndrome

for BWS. The chance for other family members to be affected in this case is expected to be low.

Approximately 10-15% of individuals who have BWS have a positive family history and a normal karyotype. Of these families, up to 50% may have an identifiable gene change in the p57 region. If a female carries this gene change, then she has a 50% chance with each pregnancy for having a child with BWS. If a male carries the gene change, the chance for having an affected child is increased, but specific risks are not yet available. Up to 50% of individuals with a positive family history and a normal karyotype do not have an identifiable gene change in the p57 region. In this situation, the chance for the parents to have another affected child is as high as 50%.

Approximately 1-2% of patients with BWS have a detectable chromosome abnormality. In patients who have a translocation or a duplication of 11p15 detected on their karyotype, the parents’ chromosome analysis should be analyzed. Depending upon the results of the parents’ chromosome analysis, there could be up to a 50% chance of having an affected child with BWS.

Demographics

The reported incidence for BWS is approximately one in 14,000, although this is likely to be an underestimate because of undiagnosed cases. BWS is not found more commonly in any particular sex or geographic region and has been reported in a wide variety of ethnic backgrounds.

Signs and symptoms

Major signs or symptoms include: macrosomia, macroglossia, abdominal wall defect, visceromegaly, embryonal tumors, hemihyperplasia, ear lobe creases or ear pits, renal abnormalities, and rarely cleft palate.

Minor signs and symptoms include: polyhydramnios, prematurity, neonatal hypoglycemia, advanced bone age, heart defects, hemangioma, facial nevus flammeus, and the characteristic facial features, which include underdeveloped midface and possible soft-tissue folds under the eyes.

Diagnosis

BWS is diagnosed primarily by the identification of clinical signs and symptoms. Although there is no official diagnostic criteria for BWS, most would agree that a diagnosis requires the presence of three major findings, or at least two major findings and one minor finding. For the purposes of diagnosis, a major finding would also include a family history of BWS.

When considering the diagnosis of BWS, several other syndromes should also be considered (differential diagnosis). These include, but are not limited to, infant of a diabetic mother, Simpson-Golabi-Behmel syndrome, Perlman syndrome, Sotos syndrome, and Costello syndrome.

If a couple has had a child affected with BWS and an identifiable gene change in the p57 region has been identified, or if a chromosome abnormality is detected by chromosome analysis, then prenatal testing through chorionic villus sampling or amniocentesis is possible. If this is not possible, then potentially, detailed ultrasound examination could help to reassure parents that the signs and symptoms of BWS are not present (such as omphalocele, macroglossia, and macrosomia). If any of these signs or symptoms are present, and the couple has had a previously affected child, then it would be very likely that the present pregnancy is affected as well.

If a couple has not had a previously affected child and has had an ultrasound examination that identifies an omphalocele, then chromosome analysis should be offered to rule out a chromosome abnormality and to look for the abnormal chromosome findings associated with BWS. If chromosome results are normal, BWS is still a possible cause for the ultrasound findings.

Treatment and management

Early treatment of hypoglycemia is important to reduce the risk of central nervous system damage. Most cases of hypoglycemia are mild and will resolve shortly with treatment, however, some cases may be more difficult to treat. Treatment for hypoglycemia may include steroid therapy, which is usually required for only one to four months.

If an infant has an abdominal wall defect, such as an omphalocele, surgery is usually performed soon after birth to repair the defect. For very large omphaloceles, a multi-stage operation is performed. The treatment and management of the omphalocele depends upon the presence of other problems and is very specific to each individual.

A cardiac evaluation is recommended prior to surgery or if a heart defect is suspected by clinical evaluation. Cardiomegaly is frequently present, but usually resolves without treatment.

Non-malignant kidney abnormalities, including renal cysts and hydronephrosis, occur in approximately 25% of patients. A consult with a pediatric nephrologist would be recommended for patients who have structural renal abnormalities, including any evidence of renal calcium deposits on ultrasound examination.

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To screen for tumors, a baseline magnetic resonance imaging or computed tomography (CT) examination of the abdomen is recommended for individuals believed to have BWS. To screen for Wilms tumor and other embryonal tumors, abdominal ultrasound is recommended. Blood pressure should also be monitored, as approximately 50% of people with Wilms tumors may have associated hypertension. Because tumor development may occur at any time, though usually before eight years of age, the screening recommendations are that abdominal ultrasound be performed every three to six months until eight years of age, and then annually until growth is complete. In addition to ultrasound, screening for hepatoblastoma is accomplished by serial measurements of the serum alpha-fetoprotein (AFP) levels during these years as well. Elevated levels of serum AFP are present 80-90% of the time when a hepatoblastoma is present. Alpha-feto- protein is a protein produced by the fetal liver. Concentrations of this protein fall rapidly during the first few weeks after birth and reach adult levels by six months of age. These adult levels are approximately 2-20 ng/ml. Thus, the presence of elevated levels in children and adults usually indicates tumor development. Abnormal AFP levels should be followed with an abdominal CT examination looking for evidence of a tumor in the liver.

Surgical removal is the primary treatment for hepatoblastoma; however, in tumors that cannot be removed, chemotherapy is performed.

Treatment for Wilms tumor is often only surgical removal of the tumor; however, in some cases chemotherapy and radiation therapies are necessary, depending upon the stage of disease and the characteristics of the tumor.

Macroglossia may need to be addressed with the possibility of surgery. The large tongue may partially block the respiratory tract and lead to problems such as difficulty breathing and feeding. In most cases, the tongue growth slows over time and eventually the tongue can be accommodated. Dental malocclusion and a prominent jaw are secondary to the macroglossia. In rare cases, surgery to reduce tongue size is needed and is usually performed between two and four years of age.

Prognosis

After dealing with initial neonatal issues such as hypoglycemia, feeding, and respiratory problems, prognosis is usually good. Infants with BWS syndrome have an approximately 20% mortality rate. This is mainly due to complications stated above, and also includes complications of prematurity and omphalocele. The prognosis with repaired omphalocele is good. The majority of deaths in cases of omphalocele are usually associated with other anomalies or respiratory insufficiency.

Respiratory insufficiency can occur in patients with omphaloceles if the omphalocele is so large that prenatal lung development cannot occur as usual. Respiratory insufficiency can also occur because of prematurity.

Tumor survival rates for Wilms tumor and for hepatoblastoma are as follows. In general, the four-year survival of all patients who have Wilms tumor with favorable histology approaches 90%. For hepatoblastomas, the combination of surgery and chemotherapy has achieved disease-free survival rates of 100% for stage I, 75% for stage II, and 67% for stage III hepatoblastomas.

In children who have BWS, development is usually normal if there is no history of significant, untreated hypoglycemia. After childhood, complications for patients with BWS are uncommon and prognosis is good.

Resources

BOOKS

Jones, Kenneth Lyons. Smith’s Recognizable Patterns of

Human Malformation. W.B.Saunders Company, 1997.

ORGANIZATIONS

Beckwith-Wiedemann Support Network. 2711 Colony Rd., Ann Arbor, MI 48104. (734) 973-0263 or (800) 837-2976.http://www.beckwith-wiedemann.org .

Renee A. Laux, MS

Berlin breakage syndrome see Nijmegen breakage syndrome

Beta-galactosidase-1 deficiency see Gm1 gangliosidosis

I Beta thalassemia

Definition

Beta thalassemia is an inherited disorder that affects the beta globin (protein molecules) chains. These chains are required for the synthesis of hemoglobin A (a compound in the blood that carries oxygen to the cells and carbon dioxide away from the cells). A decrease of beta globin chains causes early destruction of the red blood cells. There are four types of the disorder and they range in severity of symptoms.

The thalassemias were first discovered by Thomas Cooley and Pearl Lee in 1975. Early cases of the disease were reported in children of Mediterranean descent and therefore the disease was named after the Greek word for sea, thalasa.

thalassemia Beta

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Beta thalassemia

Description

Beta thalassemia results due to a defect in the beta globin gene. Shortly after birth, the body converts from producing gamma globin chains, which pair with alpha globin chains to produce fetal hemoglobin (HbF), to producing beta globin chains. Beta globin chains pair with alpha globin chains to produce adult hemoglobin (HbA). Due to the decreased amount of beta globin chains in individuals with beta thalassemia, there is an excess of free alpha globin chains. The free alpha globin chains become abnormal components in maturing red blood cells. This leads to destruction of the red blood cells by the spleen and a decreased number of red blood cells in the body. Individuals with beta thalassemia may continue producing gamma globin chains in an effort to increase the amount of HbF and compensate for the deficiency of HbA.

There are four types of beta thalassemias. These include beta thalassemia minima, minor, intermedia, and major. Beta thalassemia minima and beta thalassemia minor are less severe and usually asymptomatic. Beta thalassemia minima is known as the silent form of the disorder. There are no major hematologic (blood and blood forming tissue) abnormalities. The only noted abnormality is the decrease in beta globin production. Beta thalassemia minor is rare. A person with this type of the disorder inherits only one beta globin gene. Although children are usually asymptomatic, they do have abnormal hematologic (blood) findings.

Beta thalassemia intermedia and major often require medical treatment. Beta thalassemia intermedia is frequently found during the toddler or preschool years. It is considered to be the mild form of thalassemia major and usually does not require blood transfusions. Thalassemia major is typically diagnosed during the first year of life. There are two designations for beta thalassemia major, beta zero and beta positive. In type beta zero there is no adult hemoglobin (HbA) present due to the very small production of beta globin. In type beta positive there is a small amount of HbA detectable. In both forms of beta thalassemia major, individuals will experience severe fatigue due to the decrease or absence of adult hemoglobin (HbA), which is needed to carry oxygen to the cells, and is necessary for cellular survival.

Alternate names associated with beta thalassemia minor include thalassemia minor, minor hereditary leptocyosis, and heterozygous beta thalassemia. Alternate names associated with beta thalassemia intermedia include intermedia Cooley’s anemia and thalassemia intermedia. Alternate names associated with beta thalassemia major include Cooley’s anemia, erythroblas-

toic anemia of childhood hemoglobin lepore syndrome, major hereditary leptocytosis, Mediterranean anemia, mocrocythemia, target cell anemia, and thalassemia major.

Genetic profile

Beta thalassemia is an autosomal recessive disorder. A person who is a carrier will not develop the disorder but may pass the gene for the disorder onto their child. There is a 25% chance for each pregnancy that the disorder will be passed onto the children if both parents are carriers for the trait and a 100% chance if both parents have the trait.

Individuals with thalassemia minor are carriers for the beta globin gene and therefore possess only one of the genes necessary to express the disorder. These individuals are usually asymptomatic or have very few symptoms. Individuals with thalassemia major express both abnormal genes for beta globin and therefore will have the disease. These individuals show severe symptoms for the disorder.

The beta globin gene is found on chromosome 11. Mutations (inappropriate sequence of nucleotides, the building blocks of genes) resulting in beta thalassemia are usually caused by substitutions (switching one nucleotide for another) although some may be caused by deletions (part of a chromosome, a structure that places genes in order, is missing). Substitutions occur within the nucleotide and deletions occur on the chromosome that the beta globin gene is found on.

Demographics

Beta thalassemia affects males and females equally. It commonly occurs in people of Mediterranean heritage. It is also found in families descending from Africa, the Middle East, India, and Southeastern Asia.

Signs and symptoms

Symptoms for beta thalassemia vary in severity based on the type of the disorder.

Beta thalassemia minima

There are no symptoms for this type. It is considered to be a “silent” form of beta thalassemia.

Beta thalassemia minor

Individuals with this type of beta thalassemia may be asymptomatic or experience very few symptoms. Symptoms may be worse in individuals that are pregnant, under stress, or malnourished. Symptoms may include:

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Fatigue. This may be the only symptom that an individual with beta thalassemia minor exhibits. Fatigue is caused by the decreased oxygen carrying capacity of the red blood cells, resulting in lowered oxygenation for cells and tissues.

Anemia. Anemia is a decrease in the amount of hemoglobin in the blood. Hemoglobin is needed to carry oxygen on the red blood cells. In beta thalassemia minor there is a decrease in adult hemoglobin (HbA) and an increase in hemoglobin A2. Hemoglobin A2 is a minor hemoglobin that contains delta globin chains in the place of beta globin chains. Anemia is most likely to occur during pregnancy.

Splenomegaly. Enlargement of the spleen may occur due to increased removal of defective red blood cells. This is rarely seen in individuals with beta thalassemia minor and may be accompanied by pain in the upper left portion of the abdomen.

Skin. The skin color of individuals with beta thalassemia minor may be pale (pallor) due to oxygen deprivation in blood.

Beta thalassemia intermedia

Individuals with this form of beta thalassemia usually begin to show symptoms during toddler or preschool years. These individuals present with many of the same symptoms as beta thalassemia major, however, symptoms for beta thalassemia intermedia are less severe and may include:

Anemia. In individuals with beta thalssemia intermedia, hemoglobin levels are greater than 7g/dl but they are less than normal. Normal levels for hemoglobin are 1318 for males and 12-16 for females.

Hyperbilirubinemia. Bilirubin is a yellow pigment of bile that is formed by the breakdown of hemoglobin in the red blood cells. Excess amounts of bilirubin in the blood is caused by the increased destruction of red blood cells (hemolysis) by the spleen.

Splenomegaly. Enlargement of the spleen is caused by increased removal of defective red blood cells. Red blood cells are defective due to the increased amount of inclusion bodies caused by circulation of free alpha globin chains.

Hepatomegaly. Enlargement of the liver may be caused by a build-up of bile due to increased amounts of bilirubin in the blood.

Additional abnormalities. Individuals with beta thalassemia intermedia may have a yellow discoloration (jaundice) of the skin, eyes, and mucous membranes caused by increased amounts of bilirubin in the blood. Individuals may also suffer from delayed growth and abnormal facial appearance.

Beta thalassemia major

Individuals with this form of beta thalassemia present with symptoms during the first year after birth. Symptoms are severe and may include:

Severe anemia. Individuals with beta thalassemia major suffer from a hemoglobin level of less than 7 mg/dl.

Hyperbilirubinemia. Individuals will have an increased amount of bilirubin in the blood. This is due to the increased destruction of red blood cells (hemolysis) by the spleen.

Jaundice. Individuals may experience a yellow discoloration of the skin, eyes, and mucous membranes caused by increased amounts of bilirubin in the blood.

Extramedullary hematopoiesis. Abnormal formation of red blood cells outside of the bone marrow may occur in the body’s attempt to compensate for decreased production of mature red blood cells. This can cause masses or the enlargement of organs, which may be felt during physical examination.

Splenomegaly. Enlargement of the spleen may result due to increased destruction of red blood cells and the occurrence of extramedullary hematopoiesis.

Hepatomegaly. Enlargement of the liver may result due to accumulation of bile or the occurrence of extramedullary hematopoiesis.

Cholithiasis. This is the presence of stones in the gallbladder, which may lead to blockage and cause bile to be pushed back into the liver.

Bone marrow expansion. The bone marrow becomes expanded due to the increase of the production of red blood cells (erythropoiesis) in an attempt to produce more mature red blood cells and decrease the anemic state of the body.

Facial changes. Due to expansion of the bone marrow, children will develop prominent cheekbones, depression of the nasal bridge, and protrusion of the upper jaw. These facial changes are a classic sign in children with untreated beta thalassemia.

Iron overload. Iron overload of the tissues can be fatal and is due to erythroid (red blood cell) expansion. The increased destruction of a vast amount of red blood cells causes increased amounts of iron to be released from the hemoglobin.

Cardiovascular abnormalities. Accumulation of iron deposits in the heart muscle can lead to cardiac abnormalities and possibly cardiac failure.

Additional abnormalities. Individuals may also suffer from pale skin, fatigue, poor feeding, failure to thrive, and decreased growth and development.

thalassemia Beta

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Beta thalassemia

KEY TERMS

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.

Bone marrow—A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones. Bone marrow is the site of blood cell generation.

Globin—One of the component protein molecules found in hemoglobin. Normal adult hemoglobin has a pair each of alpha-globin and beta-globin molecules.

Hemoglobin—Protein-iron compound in the blood that carries oxygen to the cells and carries carbon dioxide away from the cells.

Hepatomegaly—An abnormally large liver. Splenomegaly—Enlargement of the spleen.

Diagnosis

Completing a family history, performing a complete physical examination, and results of blood (hematological) tests can lead to a diagnosis of beta thalassemia. Bone abnormalities and masses or enlarged organs may be recognized during physical examination. Prenatal testing to detect beta thalassemia can be done by completing an amniocentesis (obtaining a sample of amniotic fluid, which surrounds the fetus during pregnancy). Lab results will vary depending on the type of beta thalassemia that an individual presents with.

Normal hemoglobin results are 13–18 g/dl for males and 12–16 g/dl for women. Normal red blood cell counts are 4.7–6.1 million for males and 4.2–5.4 million for females. In individuals with beta zero form of beta thalassemia major, there will be no HbA present in the blood.

Symptoms of beta thalassemia minor may be similar to those of sideroblastic anemia (a disorder characterized by low levels of hemoglobin, fatigue, and weakness) and sickle cell disease (a disease that changes red blood cell shape, rendering it incapable of functioning).

Symptoms of beta thalassemia major may be similar to those of hereditary spheocytic hemolytic anemia (presence of sphere shaped red blood cells).

Treatment and management

Beta thalassemia minima and minor usually require no treatment. Pregnant women that suffer from beta tha-

lassemia minor may require blood transfusions to keep hemoglobin levels normal. Individuals with beta thalassemia intermedia and major can be treated with blood transfusions and iron chelation (binding and isolation of metal) therapy. Although individuals with beta thalassemia intermedia do not usually require transfusions, in certain cases it may be necessary.

Blood transfusions are performed in individuals that present with severe symptoms such as anemia and impaired growth and development. Children may receive transfusions every four to six weeks. A high risk associated with transfusions is iron overload, which is fatal. Iron overload results due to inadequate amounts of serum transferring (a molecule that exchanges iron between body tissues), which is needed to bind and detoxify iron. Iron accumulation can lead to dysfunction of the heart, liver, and endocrine glands.

Monitoring iron levels in the body is essential. Individuals receiving blood transfusions should keep total body iron levels at 3–7 mg of iron per gram of body weight. As of 2000, there are three methods of measuring iron levels in the body. These include a serum ferritin test, liver biopsy, and radiological study performed by the Superconducting Quantum Interference Device (SQUID).

The serum ferritin (iron storage protein) test is completed by testing a blood sample for ferritin content. This method is the easiest and most affordable way of testing for body content of iron, but it is not reliable. A liver biopsy is an invasive procedure that requires removal of a small piece of the liver. Studies have shown that a liver biopsy is very accurate in measuring the level of iron stores in the body. The third method, which requires a Superconducting Quantum Interference Device, is also very accurate in measuring iron stores. The SQUID is a highly specialized machine and few centers in the world possess this advanced technology.

Iron overload can be prevented with the use of iron chelating therapy. Chelating agents attract the excess iron and assist with the process of binding and detoxifying this iron in the body. The drug deferoxamine (desferol) is one of the most widely used iron chelating agents. Treatment is completed through nightly infusions of deferoxamine by a pump or with daily intramuscular injections. Infusion by pump is used for the administration of high doses and low doses are given through injections. Iron chelation therapy by oral administration with a drug named deferiprone has been under experimental study and may be an alternative to deferoxamine.

Individuals receiving blood transfusions should pay close attention to iron intake in the diet. It is recom-

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mended that children under age 10 keep dietary iron intake at 10 mg/day or less. Individuals age 11 or older should keep dietary iron intake at 18 mg/day or less. Foods high in iron include: beef, beans, liver, pork, peanut butter, infant cereal, cream of wheat, prunes, spinach, raisins, and leafy green vegetables. Individuals should read food labels and avoid using cast iron cookware, which can provide more iron in food during cooking.

Increased amounts of iron in the body can cause a decrease in calcium levels that can impair organs which aid in building strong bones. Individuals with beta thalassemia major are at risk for developing osteoporosis (disease resulting in weakened bones). Increased dietary intake of calcium and vitamin D can help increase the storage of calcium in the bones, thus making the bones stronger and decreasing the risk for osteoporosis.

Bone marrow transplantation is another form of treatment for beta thalassemia. Outcomes of transplantation are greatly influenced by the health of the individual. This form of treatment is only possible if the individual has a suitable donor.

Researchers are investigating the use of the drugs hydroxyurea and butyrate compounds to increase the amounts of fetal and total hemoglobin in individuals with beta thalassemia. Studies using gene therapy, such a stem cell replacement, are also being conducted.

Social and lifestyle issues

Children with beta thalassemia major that is not diagnosed and treated early may develop changes in the bone structure of the face due to the expansion of bone marrow. Supportive counseling may benefit children who feel inadequate or refuse to participate in social activities due to their appearance.

Adolescents may require counseling concerning the effects that blood transfusions and iron chelation therapy may have on their social lifestyle.

Parents may need to seek counseling or attend support groups that focus on the time demand and lifestyle changes of caring for a child diagnosed with beta thalassemia.

Resources

BOOKS

Bowden, Vicky R., Susan B. Dickey, and Cindy Smith Greenberg. Children and Their Families: The continuum of care. Philadelphia: W.B. Saunders Company, 1998.

“Thalassemias.” In Principles and Practice of Medical Genetics, Volume 2, edited by Alan E.H. Emery, MD, PhD, and David L. Rimoin, MD, PhD. New York: Churchill Livingstone, 1983.

Thompson, M.W., R. R. McInnus, and H. F. Willard. Thompson and Thompson Genetics in Medicine, Fifth Edition. Philadelphia: W.B. Saunders Company, 1991.

PERIODICALS

Angelucci, E., et al. “Hepatic iron concentration and total body iron stores in Thalassemia Major”. The New England Journal of Medicine 343, (2000): 327-331.

Mentzer, W. C., et al. “Prospects for research in hematologic disorders: sickle cell and thalassemia”. The Journal of The American Medical Association 285 (2001): 640-642.

Olivieri, N. F. “The Beta Thalassemias”. The New England Journal of Medicine 341 (1999): 99-109.

Olivieri, N. F., et al. “Treatment of thalassemia major with phenylbuyrate and hydroxyurea”. The Lancet 350 (1997): 491-492.

ORGANIZATIONS

Children’s Blood Foundation. 333 East 38th St., Room 830, New York, NY 10016-2745. (212) 297-4336. cfg@nyh.med.cornell.edu.

Cooley’s Anemia Foundation, Inc. 129-09 26th Ave. #203, Flushing, NY 11354. (800) 522-7222 or (718) 321-2873.http://www.thalassemia.org .

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. http://www.modimes

.org .

National Heart, Lung, and Blood Institute. PO Box 30105, Bethseda, MD 20824-0105. (301) 592-8573. nhlbiinfo @rover.nhlbi.nih.gov. http://www.nhlbi.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 .

Laith F. Gulli, MD

Tanya Bivens, BS

valve aortic Bicuspid

Prognosis

Prognosis for beta thalassemia is good for individuals diagnosed early and those who receive proper treatment. Children with beta thalassemia major live 20-30 years longer with treatment by blood transfusions and iron chelation therapy.

I Bicuspid aortic valve

Definition

Bicuspid aortic valve is the most common malformation of the heart valves. In this type of deformity, the aortic valve has only two cusps, which are rigid points

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Bicuspid aortic valve

such as that seen on leaves, instead of the three cusps normally present. This condition may lead to abnormalities in the flow of blood from the heart to the aorta, leading to changes in the function of the heart and lungs. Treatment consists of surgical repair or replacement of the valve.

Description

A valve is a device that allows a fluid to flow in only one direction in a defined path, thereby preventing backflow of the fluid. The heart has four such valves, which allow the blood to flow in an orderly pattern through each of the four chambers of the heart and out into the largest artery of the body, the aorta. The aorta, in turn, branches into other blood vessels in the neck, limbs, and organs of the body to supply it with oxygenated blood.

The aortic valve divides the left ventricle of the heart and the aorta. It is the last valve before blood leaves the heart and passes into the aorta. The valve is formed during pregnancy and is normally composed of three separate cusps or leaflets, which, when closed, form a tightly sealed barrier that prevents backflow of blood from the aorta into the heart. Thus, when the heart contracts or pumps, the aortic valve opens and allows blood to pass from the heart into the aorta, and when the heart relaxes, the aortic valve closes and prevents backflow of blood from the aorta into the heart.

The three-cusp structure of the valve is essential for its proper function, and was noted as far back as the fifteenth century when the great master of the High Renaissance, Leonardo da Vinci, reported on his observations of anatomy and blood circulation. In bicuspid aortic valve, the aortic valve fails to form properly during development in the womb; for reasons that are unclear, two of the three cusps fail to separate properly and remain attached along one edge, resulting in an aortic valve with only two cusps.

The bicuspid aortic valve is the most common heart valve defect at birth, and many people live a normal life without even being aware of this condition. Unfortunately, bicuspid aortic valves are also more prone to disease than the normal three cusped valves. Over the years, conditions such as restricted blood flow to the aorta (aortic stenosis), backflow of blood from the aorta into the heart (aortic regurgitation, or aortic insufficiency) and valve infection (endocarditis) are often detected with associated symptoms during the adult years as progressive damage is done to the bicuspid aortic valve.

Other conditions that may occur with bicuspid aortic valve include aneurysm of the aorta (ballooning out of the aorta wall), and aortic dissection (a life-threatening split in the layers of the aorta).

Genetic profile

Most occurrences of bicuspid aortic valve appear to be sporadic (i.e., random, and not associated with a inherited defect) and are not passed on from parent to child. However, there have been some reports that the valve malformation appears in multiple members of the same family. In at least one report, this familial occurrence appears to be inherited in an autosomal dominant pattern with reduced penetrance (not showing the malformation, despite possessing the genetic cause for it). However, if there is some sort of genetic or inherited cause in some patients with bicuspid aortic valve, it has not been identified. For purposes of genetic counseling, bicuspid aortic valve can be regarded as a sporadic condition with an extremely low risk of being transmitted from parent to child.

Demographics

Bicuspid aortic valve has been reported to occur in 1-2% of the general population, and is the most common valve defect diagnosed in the adult population, accounting for up to half of the operated cases of aortic stenosis. For reasons that are unclear, bicuspid aortic valve is three to four times more likely in males than in females, though some researchers suggest that the condition may simply be diagnosed more in males because of the higher rates of calcium deposits in men that bring the aortic valve to medical attention.

Interestingly, bicuspid aortic valve is also found with other conditions, including the genetic disorder Turner’s syndrome, or in patients with a malformation called coarctation of the aorta (narrowing of the aorta). It has been reported that approximately 35% of patients with Turner’s syndrome and up to 80% of patients with coarctation of the aorta have an associated bicuspid aortic valve. The significance of these associations is unclear.

Signs and symptoms

Many people with bicuspid aortic valve experience no symptoms, and may live their entire lives unaware of the condition. However, progressive damage or infection of the valve may lead to three serious conditions: aortic stenosis, aortic regurgitation, or endocarditis.

As a person ages, calcium deposits on a bicuspid aortic valve making it stiff. Eventually, the valve may become so stiff that it does not open properly, making it more difficult for blood to leave the heart and pass into the aorta and resulting in aortic stenosis. When this blockage becomes serious enough, people may experience shortness of breath, chest pain, or fainting spells. These symptoms usually begin between the ages of 50

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and 60 years old. Eventually, the blockage can become so bad that blood backs up in the heart and lungs instead of going out to supply the rest of the body with oxygen (congestive heart failure). Additionally, this condition can lead to thickening of the heart wall, which may cause abnormal heart rhythms leading to sudden death.

Aortic regurgitation results when the valve fails to close properly. People who develop this condition may become short of breath when exerting themselves. The extent of symptoms experienced by the patient depends on the severity of the aortic regurgitation.

Finally, bacteria may deposit on the malformed bicuspid aortic valve, causing endocarditis. People with endocarditis may have symptoms of lingering fevers, fatigue, weight loss, and sometimes damage to the kidneys or spots on their fingers and hands.

Other dangerous conditions associated with bicuspid aortic valve include aortic aneurysm and aortic dissection. People with aortic aneurysms usually do not experience symptoms unless the aneurysm ruptures, but people with aortic dissection experience tearing back pain. Aortic aneurysm rupture and aortic dissection are very dangerous and can rapidly lead to death if not promptly treated.

Diagnosis

Any of the symptoms of aortic stenosis, aortic regurgitation, or endocarditis should prompt a search for an underlying malformation of the aortic valve. Aortic stenosis or regurgitation is diagnosed by a combination of physical exam, cardiovascular tests and imaging. The earliest sign of aortic valve problems is a murmur (the sound of abnormal patterns of blood flow) heard with a stethoscope. When the valve has high levels of calcium deposits, a characteristic clicking sound can also be heard with the stethoscope just as the stiff valve attempts to open. Later signs include a large heart seen on x ray or by a special electrical test of the heart, called an ECG or EKG (electrocardiogram).

If these signs are present, it suggests that the aortic valve may be damaged. The next test to be performed is echocardiography, a method that uses ultrasound waves to look at the aortic valve, similar to the way in which ultrasound is used to look at a fetus during pregnancy. Often, only two cusps are seen on the aortic valve during the echocardiography, confirming a diagnosis of bicuspid aortic valve.

Endocarditis is diagnosed by demonstrating the presence of bacteria in the blood stream. This is performed by taking blood from the patient and growing the bacteria on plates with specialized nutrients. Skilled technicians can

KEY TERMS

Aorta—The main artery located above the heart which pumps oxygenated blood out into the body. Many congenital heart defects affect the aorta.

Aortic regurgitation—A condition in which the aortic valve does not close tightly, allowing blood to flow backwards from the aorta into the heart.

Aortic stenosis—A condition in which the aortic valve does not open properly, making it difficult for blood to leave the heart.

Autosomal dominant—A pattern of genetic inheritance where only one abnormal gene is needed to display the trait or disease.

Coarctation—A narrowing of the aorta that is often associated with bicuspid aortic valve.

Echocardiogram—A non-invasive technique, using ultrasonic waves, used to look at the various structures and function of the heart.

Electrocardiogram (ECG, EKG)—A test used to measure electrical impulses coming from the heart in order to gain information about its structure or function.

Endocarditis—A dangerous infection of the heart valves caused by certain bacteria.

Heart valve—One of four structures found within the heart that prevents backwards flow of blood into the previous chamber.

Murmur—A noise, heard with the aid of a stethoscope, made by abnormal patterns of blood flow within the heart or blood vessels.

Reduced penetrance—Failing to display a trait or disease despite possessing the dominant gene that determines it.

Sporadic—Isolated or appearing occasionally with no apparent pattern.

Stethoscope—An instrument used for listening to sounds within the body, such as those in the heart or lungs.

then use different tests to identify which species of bacteria is present so that appropriate treatment can be started. The diagnosis of endocarditis is also confirmed by using echocardiography to look for bacterial growths on the aortic valve. During the echocardiography, a bicuspid valve is often seen and explains the tendency to develop endocarditis.

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Bicuspid aortic valve

This view of a human heart specimen clearly shows the structure of a bicuspid aortic valve. (Custom Medical Stock Photo, Inc.)

Treatment and management

Most people with bicuspid aortic valve will not experience any complications or symptoms and will not require treatment. However, in patients with any complication of valve damage, as previously discussed, treatment may be necessary.

In younger patients who have aortic stenosis, a procedure can be performed in which a small balloon is inserted through one of the major blood vessels and into the aortic valve. The balloon is then inflated, creating a bigger opening for blood to pass. Alternatively, an “open heart” procedure can be performed to cut the valve into a more normal configuration. These treatments are usually temporary, and later in life the patient, as well as any adult with advanced aortic stenosis, will most likely require aortic valve replacement.

Valve replacement is an “open heart” operation where the original malformed valve is removed and replaced with a new valve. This new valve can come from a human donor who has died, or from cows or pigs, or even from another part of the patient’s heart. These valves function well, but may need to be replaced after 10 to 20 years, as they wear out. Another option is to use an artificial valve made of metal, plastic, or cloth. However,

people who receive these artificial valves need to take blood thinners every day in order to prevent blood clots from forming on the new valve.

Patients with endocarditis need to be hospitalized and treated with high does of antibiotics given through a vein for several weeks. Damage done to the valve by the bacteria may make it necessary for a valve replacement procedure to be performed after the patient has recovered from the infection.

In any case, people who have been identified as having bicuspid aortic valve should be followed regularly by a cardiologist, with possible consultation with a cardiothoracic surgeon. The function of the bicuspid aortic valve should be followed through the use of echocardiography, and the state of the heart itself should be followed by regular electrocardiograms.

It should be noted that children with aortic stenosis may not be able to engage in vigorous physical activity without the risk of cardiac arrest and should consult their physician. In addition, all people with bicuspid aortic valve should receive antibiotics prior to any dental procedure or surgery; these procedures may allow bacteria to enter the blood stream and could result in endocarditis if antibiotics are not given beforehand.

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Prognosis

Most people born with bicuspid aortic valve experience no symptoms or complications, and their lives do not differ from someone born with a normal aortic valve. In patients who do experience complications and require valve replacement, risks of the operation generally depend on age, general health, specific medical conditions, and heart function. It is better to perform the operation before any of the advanced symptoms (shortness of breath, chest pain, fainting spells) develop; in patients without advanced symptoms, the risk of a bad outcome of surgery is only 4%. If a person with advanced symptoms chooses not to undergo surgery, the risk of death within three years is more than 50%. In general, valve replacement greatly reduces the amount and severity of symptoms and allows the patient to return to their normal daily activities without discomfort after they recover from the surgery.

Resources

PERIODICALS

Braunwald, E. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: Saunders, 1999.

Cotran, R. S. Robbins Pathologic Basis of Disease. Philadelphia: Saunders, 1999. pp. 566-570.

Friedman, W. F. “Congenital Heart Disease In The Adult.” In

Harrison’s Principles of Internal Medicine , edited by A.S. Fauci. New York: McGraw-Hill, 1998.

ORGANIZATIONS

American Heart Association. 7272 Greenville Ave., Dallas, TX 75231-4596. (214) 373-6300 or (800) 242-8721. inquire@heart.org. http://www.americanheart.org .

Congenital Heart Anomalies Support, Education, and Resources. 2112 North Wilkins Rd., Swanton, OH 43558. (419) 825-5575. http://www.csun.edu/~hfmth006/chaser .

WEBSITES

“Bicuspid Aortic Valve.” OMIM—Online Mendelian Inheritance in Man. National Center for Biotechnology Information. http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/ dispmim?109730 .

Oren Traub, MD, PhD

I Biotinidase deficiency

Definition

Biotinidase deficiency is a rare inherited defect in the body’s ability to use dietary biotin, one of the B vitamins. The disease is also known as juvenile or late-onset multiple carboxylase deficiency.

KEY TERMS

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

Autosomal recessive—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

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.

Co-enzyme—A small molecule such as a vitamin that works together with an enzyme to direct a biochemical reaction within the body.

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

Gene—A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Immune system—A major system of the body that produces specialized cells and substances that interact with and destroy foreign antigens that invade the body.

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.

Description

Biotin is essential as a co-factor (co-enzyme) for the reactions of four enzymes called carboxylases. These enzymes, in turn, play important roles in the metabolism of sugars, fats, and proteins within the human body. Another key enzyme, biotinidase, recycles biotin from these reactions so it can be used again. A defect in the biotinidase gene results in decreased amounts of normal enzyme, thus preventing the reuse of biotin. In turn, this leads to a disruption of the function of the four carboxylases that depend on biotin, and results in a variety of abnormalities of the nervous system and skin. Since

deficiency Biotinidase

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