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Hemophilia A

NORD is very grateful to Nigel Key, MB, ChB, FRCP, Harold R Roberts Distinguished Professor of Medicine and Pathology and Laboratory Medicine, Director, UNC Hemophilia and Thrombosis Center, University of North Carolina at Chapel Hill, for assistance in the preparation of this report.

Synonyms of Hemophilia A

  • classical hemophilia
  • factor VIII deficiency
  • haemophilia A

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Summary
Hemophilia A, also known as classical hemophilia, is a genetic bleeding disorder caused by insufficient levels of a blood protein called factor VIII. Factor VIII is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Individuals with hemophilia A do not bleed faster or more profusely than healthy individuals, but, because their blood clots poorly, they have difficulty stopping the flow of blood from a wound. This may be referred to as prolonged bleeding or a prolonged bleeding episode. Hemophilia A can be mild, moderate or severe, depending on the baseline level of factor VIII made by that individual. In mild cases, prolonged bleeding episodes may only occur after surgery, dental procedures or trauma. In more severely affected individuals, symptoms may include prolonged bleeding from minor wounds, painful swollen bruises, and unexplained (spontaneous) bleeding into vital organs as well as joints and muscles (internal bleeding). Hemophilia A is caused by disruptions or changes (mutations) to the F8 gene on the X chromosome. This mutation may be inherited or occur randomly with no previous family history of the disorder (spontaneously). Hemophilia A is fully expressed in males only, although some females who carry the gene may have mild or, rarely, severe symptoms of bleeding. Although there is no cure for hemophilia, effective therapies have been developed; most affected individuals can lead full, productive lives by maintaining proper treatment and care.

Introduction
Hemophilia is a general term for a group of rare bleeding disorders caused by congenital deficiency of certain clotting factors. The main form of hemophilia is hemophilia A. In rare cases, hemophilia A can be acquired during life (acquired hemophilia A). Although both disorders involve deficiency of the same clotting factor, the bleeding pattern is quite different. The reason the bleeding patterns differ between these disorders is not fully understood. This report only deals with the genetic form of hemophilia A.

Symptoms

The severity and symptoms of hemophilia A can vary greatly from one person to another. Hemophilia A can range from mild to moderate to severe. Some individuals may only have slightly low levels of factor VIII; other individuals may have extremely low levels of this protein. The age of onset and frequency of bleeding episodes depend upon the amount of factor VIII protein and overall clotting ability of the blood. In most individuals, regardless of severity, bleeding episodes tend to be more frequent in childhood and adolescence than in adulthood.

It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

In mild cases, individuals may experience bruising and bleeding from the mucous membranes such as nosebleeds or bleeding from the gums. More serious, prolonged bleeding episodes may occur only after surgery or dental procedures, injury or trauma. The bleeding in such cases is out of proportion for the procedure or trauma. In many cases, individuals with mild hemophilia A may go undiagnosed until they need a surgical procedure or suffer an injury. In some cases, the first bleeding episode does not occur until well into adulthood. Individuals with a mild form of hemophilia A may go many years without a prolonged bleeding episode. Mild hemophilia A can be associated with anywhere from 5-40% factor VIII clotting activity.

Individuals with moderate hemophilia A seldom have spontaneous bleeding episodes. Spontaneous bleeding refers to bleeding episodes that occur without apparent cause (spontaneously). Individuals with moderate hemophilia A are at risk for prolonged bleeding following surgery, dental procedures, or trauma. Easy or excessive bruising may also occur. Moderate hemophilia A is often diagnosed by 5 or 6 years of age. By definition, affected individuals have 1-5% factor VIII clotting activity.

Severe hemophilia A is associated with less than 1% factor VIII clotting activity. This disorder is associated with spontaneous bleeding episodes. Such episodes often results in bleeding into the deep muscles or joints (hemarthroses), which will acutely cause pain and swelling and early restricted movement of the joint. If not treated in a timely manner or at all, bleeding may result in longer term muscle weakness and/or swelling, tightness, and restricted movement of the affected joint. Permanent joint damage from arthritis can potentially occur. The joints and muscles are the most common sites for spontaneous bleeding episodes in individuals with severe hemophilia A.

Severe cases of hemophilia A usually become apparent early during infancy and a diagnosis is often made by two years of age. Without prophylactic treatment, these infants may experience bleeding from minor mouth injuries. Common symptoms in untreated infants are large swellings or "goose eggs" that form after a bump on the head. In rare cases, infants with severe hemophilia A have extra- or intracranial bleeding following birth. Untreated infants and children may also develop hematomas under the skin. Hematomas are solid swellings or masses of congealed blood. As infants and children grow older, spontaneous joint bleeds may become more frequent.

If untreated, infants and children with severe hemophilia A may have approximately two to five spontaneous bleeding episodes per month. Without treatment, affected individuals are at risk for prolonged bleeding from minor injuries, surgery and dental procedures such as tooth extractions.

Individuals with a moderate or severe form of hemophilia A can potentially experience spontaneous bleeding into any organ system including the kidneys, the gastrointestinal tract, and the brain (intracranial bleeding). Genitourinary and gastrointestinal bleeding may respectively cause blood in the urine (hematuria) and black or bloody stools (melena, hematochezia). Intracranial bleeding may cause headaches, a stiff neck, vomiting, seizures, mental status changes including excessive sleepiness and poor arousability.

Causes

Hemophilia A is caused by disruptions or changes (mutations) of the F8 gene located on the X chromosome. Approximately 70% of cases are inherited as an X-linked recessive trait. In the remaining 30%, cases occur spontaneously (i.e. new mutation) without a previously family history of the disorder.

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females who have a disease gene present on one of their X chromosomes are "carriers" for that disorder. Carrier females usually do not display symptoms of the disorder because they have another copy of the gene which can compensate for the copy with the disease-causing change or mutation. A male has only one X chromosome and, if he inherits an X chromosome that contains a disease-causing gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome, not their X chromosome, to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.

Females have two X chromosomes, but one of the X chromosomes is "turned off" or inactivated and all of the genes on that chromosome are inactivated. Carrier females, known as heterozygotes, inherit a single copy of the disease-causing gene, such as the gene for hemophilia A, which compensates for the copy with the disease-causing or hemophilia mutation. If a female has a large proportion of the X chromosome with the unchanged gene inactivated, she may have symptoms of the disorder. Depending on the proportion of the X-chromosome with the disease-causing copy of the gene, a female may exhibit symptoms of the disorder, in this case, the mild, moderate, or severe form of hemophilia A. There are other rare mechanisms which can cause a female to have hemophilia or other conditions caused by genes on the X chromosome.

Investigators have determined that the F8 gene is located on the long arm (q) of chromosome X (Xq28). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xq28" refers to band 28 on the short arm of chromosome X. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The F8 gene contains instructions for creating (encoding) factor VIII. Factor VIII is one of the essential blood proteins and plays a role in aiding the blood to clot in response to injury. Mutations of the F8 gene result in deficient levels of functional factor VIII. The symptoms of hemophilia A occur due to this deficiency.

Affected Populations

Hemophilia A is the most common X-linked recessive disorder and the second most common inherited clotting factor deficiency after von Willebrand disease. Hemophilia A only affects males fully, although some carrier females may develop certain symptoms of the disorder. Approximately 1 in 5,000 males born has hemophilia A. Approximately 60% of individuals with hemophilia A have a severe form of the disorder. All racial and ethnic groups are equally affected by hemophilia.

Related Disorders

Symptoms of the following disorders can be similar to those of hemophilia A. Comparisons may be useful for a differential diagnosis.

Acquired hemophilia is a rare autoimmune disorder characterized by bleeding that occurs in patients with a personal and family history negative for a bleeding disorder. Autoimmune disorders occur when the body's immune system mistakenly attacks healthy cells or tissue. In acquired hemophilia, the body produces antibodies (known as inhibitors) that attack clotting factors, most often factor VIII. Consequently, affected individuals develop complications associated with abnormal, uncontrolled bleeding into the muscles, skin and soft tissue and during surgery or following trauma. Specific symptoms can include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria) and gastrointestinal or urogenital bleeding. Acquired hemophilia can potentially cause severe, life-threatening bleeding complications. In approximately 50% of cases, there is an identifiable underlying clinical condition; in the other 50% no cause is known (idiopathic). (For more information on this disorder, choose "acquired hemophilia" as your search term in the Rare Disease Database.)

Von Willebrand disease (VWD) is a genetic bleeding disorder resulting in prolonged bleeding and variable clinical manifestations. Individuals with VWD have a defect in or deficiency of a clotting protein known as von Willebrand factor (VWF). Deficient or defective VWF results in improper functioning of platelets, which are specialized blood cells that mass together to form the initial clots that stop bleeding. In individuals with VWD, platelets do not stick to the tissue around holes in blood vessels and bleeding is therefore prolonged. Defective VWF can also cause reduced levels of factor VIII. This is because VWF binds to and stabilizes factor VIII so that it is not rapidly broken down within the blood. Most people with VWD have relatively mild symptoms and are not diagnosed until they are adults. A small percentage of individuals have problems during infancy or early childhood such as prolonged bleeding after injury or surgery and/or spontaneous bleeding. Spontaneous bleeding can occur in the gastrointestinal bleeding, nosebleeds, bleeding from the gums, and easy bruising. Affected women frequently experience heavy menstrual periods, and may bleed excessively following childbirth. There are three main forms of the disorder. Most cases are inherited as autosomal dominant disorders; some cases are inherited as autosomal recessive disorders. (For more information on this disorder, choose "Von Willebrand" as your search term in the Rare Disease Database.)

Fibrinogen disorders are a group of rare bleeding disorders characterized by deficiency or absence of a certain protein in the blood that is essential in the blood clotting (coagulation) process. This protein is known as fibrinogen or coagulation factor I. Three forms have been identified: congenital afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia. Individuals with congenital afibrinogenemia may be susceptible to severe bleeding (hemorrhaging) episodes and prolonged bleeding from minor cuts. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms (asymptomatic) or may develop mild bleeding episodes. (For more information on this disorder, choose "fibrinogenemia" as your search term in the Rare Disease Database.

Inherited platelet disorders are characterized by low levels of and/or poorly functioning platelets. Platelets are tiny blood cells that clump together to form plugs at the sites of a wound. Low levels of or dysfunctional platelets result in abnormal bleeding episodes including bruising, recurrent nosebleeds (epistaxis) or mouth bleeding, gastrointestinal bleeding and excessive bleeding following some types of surgery or injury. The bleeding severity and type of symptoms vary depending upon the specific platelet disorder present. Platelet disorders include Bernard-Soulier syndrome and Glanzmann's thrombasthenia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database).

Standard Therapies

Diagnosis
A diagnosis of hemophilia A is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized laboratory tests.

Clinical Testing and Workup
Laboratories studies can include a complete blood count (CBC), coagulation tests and measurement of the level of specific factors (e.g. factor VIII). Screening coagulation tests that measure how long it takes the blood to clot include the activated partial thromboplastin time (aPTT) and prothrombin time (PT). These coagulation tests are usually normal in hemophilia A.

However, the aPTT can be prolonged, especially in cases of severe or moderate hemophilia A. In such cases, a diagnosis of hemophilia A must be confirmed through a clotting activity assay, a test that can measure the activity of certain substances in the blood. An assay can determine whether the cause of the abnormal aPTT is deficiency of factor VIII (hemophilia A), factor IX (hemophilia B), or another blood clotting factor deficiency. This specific test will also determine the severity of the factor VIII deficiency. Even if an aPTT test is normal this does not rule out mild or even moderate cases of hemophilia A because of the relative insensitivity of the test.

Once the diagnosis of hemophilia A is made, the specific abnormality in the F8 gene is often determined to ascertain the affected person's risk of developing an uncommon but serious complication, i.e. the development of resistance (an immune reaction, antibodies), sometimes accompanied by allergic reactions, to the treatment outlined below. This complication is otherwise known as "inhibitor" development, since this complication can seriously inhibit the effectiveness of standard treatment (see below).

Molecular genetic testing, which can identify mutation of the F8 gene is available on a clinical basis. Understanding the specific F8 gene mutation can also be helpful in identifying carriers in the family as well as in the prenatal diagnosis of hemophilia A in subsequent carrier pregnancies.

Treatment
Individuals with hemophilia A will benefit from referral to federally-funded hemophilia treatment centers. These specialized centers can provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow up of affected individuals, and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapist, social worker and genetic counselor) experienced in the treatment of individuals with hemophilia. Genetic counseling will be of benefit for affected individuals and their families.

Although there is no cure for hemophilia A, current treatments are very effective. Treatment consists of replacing the missing clotting protein (factor VIII) and preventing the complications associated with the disorder. Replacement of this protein may be obtained through recombinant factor VIII, which is artificially created in a lab. Many physicians and voluntary health organizations favor the use of recombinant factor VIII because it does not contain human blood. Factor VIII can also be obtained from frozen plasma (i.e., blood donations). Human blood donations do carry a risk of transmitting viral infection such as hepatitis. However, newer techniques for screening and treating blood donations have made such a risk extremely low.

The Food and Drug Administration (FDA) has approved several recombinant forms of factor VIII for the treatment of hemophilia A including Helixate®FS (CSL Behring); Recombinate® (Baxter); Kogenate®FS (Bayer HealthCare); Advate® (Baxter); ReFacto® (Pfizer); and Xyntha® (Pfizer). Human plasma-derived preparations include Monarc-M (Baxter), Monoclate-P® (CSL Behring), Hemofil M (Baxter), and Koate-DVI (Kedrion).

Individuals with mild or moderate hemophilia A may be treated with replacement therapy as needed (i.e. to treat specific bleeding episodes). This is referred to as episodic therapy. Some individuals with severe hemophilia A may receive periodic factor VIII infusions to prevent bleeding episodes and associated complications such as joint damage. This is referred to as prophylactic therapy.

Parents and affected individuals can be trained to administer infusions at home. This is especially important for individuals with severe disease because infusion of factor VIII concentrate is most effective within one hour of the onset of a bleeding episode. In general, rapid treatment is important because it reduces pain and damage to the joints, muscle or other affected tissues or organs.

Some individuals with mild hemophilia A may be treated with desmopressin (DDAVP), a synthetic agent that is a derivative of the hormone vasopressin. Desmopressin raises the plasma levels of factor VIII. Desmopressin may be administered intravenously or through a nasal spray. Drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood, can also be used to treat individuals with mild hemophilia A.

Inhibitors
In some cases (approximately 30% of individuals with severe disease), individuals with hemophilia A may develop "inhibitors" against the replacement factor VIII. Inhibitors are antibodies, which are specialized proteins created by the body's immune system to combat foreign or invading substances such as toxins or bacteria. The immune system may recognize replacement factor VIII as "foreign" and create these antibodies (inhibitors), which target and destroy the replacement factor. Inhibitor development can sometimes be accompanied by mild or serious allergic reactions. Inhibitors may also be known as alloantibodies. The reasons a person develops an inhibitor are complex, not fully understood, and most likely due to several different factors. The risk of developing an inhibitor may change during an affected individual's life. More research is necessary to determine the exact underlying mechanisms that ultimately cause inhibitor development in some individuals with hemophilia A.

An inhibitor can seriously "inhibit" the effectiveness of standard treatment. In such cases, alternate treatment is used to treat bleeding, and additional therapy to eradicate these antibodies is sometimes instituted (immune tolerance).

The amount of antibody (inhibitor) in an individual can be measured and is referred to as the titer. The inhibitor titer is expressed in a specific measurement called a Bethesda unit. The higher the number of Bethesda units, the more inhibitor that is present. An inhibitor can also be classified as low-responding or high-responding depending on how an individual's immune system is stimulated based on repeated exposure to factor VIII. If the immune response is strong, inhibitor levels can rise to high levels. This is called high-responding. Alternatively, the immune system response can be weaker; this is classified as low-responding.

If the inhibitor titer is very low (i.e. < 5 Bethesda units) and low-responding, then bleeding episodes in affected individuals can often be treated with replacement factor VIII. However, replacement factor VIII is not effective in individuals with a high inhibitor titer (i.e. > 5 Bethesda units).

In individuals with higher titer levels, bypassing agents (concentrates of factors that bypass the factor deficiency) are often used to control bleeding episodes. The bypassing agents that are presently available are recombinant activated factor VII (rFVIIa or NovoSeven® RT) or activated prothrombin complex concentrate (aPCC or FEIBA®). Neither of these therapies is effective in all individuals.

The U.S. Food and Drug Administration (FDA) has approved NovoSeven® RT, a genetically engineered (recombinant) version of activated factor VII, for the treatment of inhibitors in hemophilia A. Because it is artificially created in a lab, it does not contain human blood or plasma and, consequently, there is no risk of blood-borne viruses or other such pathogens. NovoSeven has been well-tolerated and associated with few side effects. Risk of thrombotic adverse effects (thrombosis) is below 1% for individuals with hemophilia. NovoSeven® RT is manufactured by the pharmaceutical company Novo Nordisk.

aPCC is a plasma-derived, anti-inhibitor complex that contains various activated clotting factors. These factors allow the drug to bypass certain steps in the formation of blood clots (including the steps that require factor VIII). aPCC is treated to inactivate any potential viruses or similar pathogens and adverse thrombotic events are rare. The only form of aPCC currently available in the United States is FEIBA®, which is available from Baxter Healthcare Corporation.

While the aforementioned therapies treat bleeding episodes, some individuals with inhibitors may undergo a process known as immune tolerance induction. This type of therapy is designed to eradicate the inhibitor, allowing individuals to be treated with replacement factor VIII. Immune tolerance induction involves exposing an affected individual to high doses of replacement factor VIII over a period of time that can range from months to years. The process is designed to train the immune system to accept therapy with replacement factor VIII without producing more inhibitors. Drawbacks to immune tolerance induction are cost, inconvenience and that it is time-consuming. However, immune tolerance induction has proven effective in eradicating inhibitors in approximately 70-80% of cases.

Investigational Therapies

Gene therapy is also been studied as another approach to therapy for individuals with hemophilia. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a "cure." However, at this time, there remain some technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

Contact for additional information about hemophilia A:

Nigel Key, MB, ChB, FRCP
Harold R Roberts Distinguished Professor of Medicine and Pathology and Laboratory Medicine
Director, UNC Hemophilia and Thrombosis Center
University of North Carolina at Chapel Hill
919-966-3311
nigel_key@med.unc.edu

Organizations related to Hemophilia A

References

TEXTBOOKS
Hilgartner WM. The Hemophilias. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:390-391.

JOURNAL ARTICLES
Srivastava A, Brewer AK, Mauser-Bunschoten EP. Guidelines for the management of hemophilia. Haemophilia. 2012;[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/22776238

Scott DW, Lozier JN. Gene therapy for haemophilia: prospects and challenges to prevent or reverse inhibitor formation. Br J Haematol. 2012;156:295-302. http://www.ncbi.nlm.nih.gov/pubmed/22055221

Witmer C, Presley R, Kulkarni R, et al. Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States. Br J Haematol. 2011;152:211-216. http://www.ncbi.nlm.nih.gov/pubmed/21114482

Kempton CL. Inhibitors in previously treated patients: a review of the literature. Haemophilia. 2011;16:61-65. http://www.ncbi.nlm.nih.gov/pubmed/20536987

Franchini M, Lippi G. Immune tolerance induction for patients with severe hemophilia A: a critical literature review. J Thromb Thrombolysis. 2011;32:439-437. http://www.ncbi.nlm.nih.gov/pubmed/21818664

Butros L, Boayue K, Mathew P. Current difficulties and recent advances in bypass therapy for the management of hemophilia with inhibitors: a new and practical formulation of recombinant factor VIIa. Drug Des Devel Ther. 2011;5:275-282. http://www.ncbi.nlm.nih.gov/pubmed/21625417

Kruse-Jarres R. Current controversies in the formation and treatment of alloantibodies to factor VIII in congenital hemophilia A. Hematology Am Soc Hematol Educ Program. 2011;2011:407-412. http://www.ncbi.nlm.nih.gov/pubmed/22160066

Pipe S. Visions in haemophilia care. Thromb Res. 2009;124:S2-S5. http://www.ncbi.nlm.nih.gov/pubmed/20109652

Goodeve A. Molecular genetic testing of hemophilia A. Semin Thromb Hemost. 2008;34:491-501. http://www.ncbi.nlm.nih.gov/pubmed/19085648

Key NS. Inhibitors in congenital coagulation disorders. Br J Haematol. 2004;127:379-391. http://www.ncbi.nlm.nih.gov/pubmed/15521914

Peyvandi F, Jayandharan G, Chandy M, et al. Genetic diagnosis of haemophilia and other inherited bleeding disorders. Haemophilia. 2006;12:82-89. http://www.ncbi.nlm.nih.gov/pubmed/16684001

INTERNET
Konkle BA, Josephson NC, Nakaya Fletcher SM, Thompson AM. Updated:09/22/2011. Hemophilia A. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1404/

Zaiden RA, Jardine LF, Lorenzana A, et al. Hemophilia A. Emedicine Journal, Novemeber 15 2011. Available at: http://emedicine.medscape.com/article/779322-overview Accessed on: April 5, 2012.

DiMichele D. Inhibitors in hemophilia: a primer, 4th ed. World Federation of Hemophilia. April 2008. Available at: http://www.wfh.org/2/docs/Publications/Inhibitors/TOH-7%20Inhibitor-Primer-Revised2008.pdf Accessed On: April 5, 2012.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:306700; Last Update:04/12/2012. Available at: http://omim.org/entry/306700 Accessed on: April 12, 2012.

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Report last updated: 2012/08/09 00:00:00 GMT+0

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