Information on the following diseases can be found in the Related Disorders section of this report:

• May-Hegglin Anomaly
• Hemophilia
• Essential Thrombocytopenia
• Thrombasthenia of Glanzmann and Naegeli
• Von Willebrand Disease
• Storage Pool Disease
• Platelet Disorders (General)

The symptoms of Bernard-Soulier Syndrome, which are typically apparent at birth and continue throughout life, may include the tendency to bleed excessively from cuts and other injuries, nosebleeds (epitaxis), and/or an unusually heavy menstrual flow in women. People with this disease also bruise easily and the bruises tend to linger. Bleeding from very small blood vessels under the skin (subcutaneous) may cause small or widespread areas of small red or purple colored spots (purpura).

BSS is a genetic disorder that affects the ability of the platelets in the circulating blood to bind with a damaged vessel and hence to clot blood. These platelets are missing an essential protein called glycoprotein Ib-IX-V (GPIb) that normally sticks out of the platelet’s surface and binds with another protein found in the circulating blood called von Willebrand factor. If one of these proteins is missing or abnormal, they cannot bind correctly to begin the clotting process and excessive bleeding results.

BSS is caused by a mutation in any one of four genes for the GPIb protein. The abnormal genes have been mapped to chromosomes 17p12, 22q11.2, 3q21 and 3q29.

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 17p12” refers to band 12 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Bernard-Soulier Syndrome is usually inherited as an autosomal recessive genetic trait.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Bernard-Soulier Syndrome is a rare bleeding disorder that affects males and females in equal numbers. Approximately 100 cases have been reported.
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Symptoms of the following disorders can be similar to those of Bernard- Soulier Syndrome. Comparisons may be useful for a differential diagnosis:

May-Hegglin Anomaly is a rare inherited disorder of blood platelets and certain white blood cells characterized by abnormally large platelets. Some people with this disorder have symptoms from birth while others are without symptoms for life. Symptoms may include nosebleeds, purple colored spots on the skin (purpura), excessive bleeding from the mouth during dental work, and/or headaches. Some people with May-Hegglin Anomaly may experience muscular weakness on one side of the body because of abnormal bleeding inside the brain (intracranial hemorrhage). (For more information on this disorder, choose "May-Hegglin" as your search term in the Rare Disease Database.)

Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that enables the blood to clot. Hemophilia is found in males almost exclusively and can be classified as mild, moderate, or severe depending upon the percentage of clotting factor present in a person's blood. The most serious symptom of Hemophilia is uncontrolled internal bleeding that may begin spontaneously without any apparent cause. Internal bleeding may cause permanent damage to the joints and muscles. People with Hemophilia bleed for a longer period of time than people who have the normal percentage of active clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in males with this disorder. (For more information on this disorder, choose "Hemophilia" as your search term in the Rare Disease Database.)

Essential Thrombocytopenia is a rare blood platelet disorder characterized by an abnormally small number of circulating platelets that survive for a shorter than normal period of time. The major symptom is excessive bleeding, especially under the skin, in the eyes, and in the mucous membranes of the mouth. In severe cases of Essential Thrombocytopenia abnormal bleeding may occur in the brain (intracranial hemorrhage). People with this disorder bruise easily and may also have sudden nosebleeds. Many small red or purple spots (petechiae) may appear on the skin, especially around the ankles and feet. (For more information on this disorder, choose "Essential Thrombocytopenia" as your search term in the Rare Disease Database.)

Thrombasthenia of Glanzmann and Naegeli is a rare inherited blood clotting (coagulation) disorder characterized by impaired function of the specialized red blood cells (platelets) that are essential for proper blood clotting. Symptoms may include abnormal bleeding and/or hemorrhage, easy bruising, bleeding from the gums, nosebleeds (epitaxis), and/or large red or purple colored spots on the skin (purpura). The symptoms of Thrombasthenia of Glanzmann and Naegeli are not progressive and may improve with age. (For more information on this disorder, choose "Thrombasthenia" as your search term in the Rare Disease Database.)

Von Willebrand Disease is a rare inherited blood clotting (coagulation) disorder that occurs during infancy or early childhood and is characterized by prolonged bleeding and an abnormally slow blood clotting time. Symptoms may include bleeding from the gastrointestinal tract, nosebleeds, bleeding from the gums, and/or easy bruising. People with this disorder may also bleed easily after injury, childbirth, and/or surgery. These symptoms occur because of a deficiency of factor VIII and the von Willebrand factor. (For more information on this disorder, choose "von Willebrand" as your search term in the Rare Disease Database.)

Storage Pool Disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets' inability to store certain clotting factors. Symptoms occur mostly in women and may include mild bleeding, nosebleeds, and/or slightly heavier than normal menstrual periods. People with Storage Pool Disease may also have abnormally low levels of blood platelets (thrombocytopenia).

Platelet disorders are also associated with congenital conditions such as Wiskott-Aldrich Syndrome, Down Syndrome, and Thrombocytopenia with Absent Radius Syndrome. For more information on these disorders choose "Wiskott- Aldrich," "Down Syndrome," and "Thrombocytopenia with Absent Radius," as your search terms in the Rare Disease Database.)

Diagnosis
The diagnosis of Bernard-Soulier syndrome is made by a combination of blood testing to reveal whether platelets are at abnormally low levels (thrombocytopenia); microscopic examination to determine the presence of abnormally large platelets and irregularly shaped platelets; and biochemical tests to determine the capacity of the platelets to initiate clotting.

Treatment
Platelet transfusion is used to treat Bernard-Soulier syndrome when surgery is necessary or when there is a risk for life-threatening hemorrhage. People with this disorder should not take aspirin or other related drugs because these medications affect the blood's ability to clot (platelet aggregation). It is suggested that acetaminophen, which is present in medications such as Tylenol, be used for the relief of mild pain.

Genetic counseling may be of benefit for people with Bernard-Soulier syndrome and their families. Other treatment is symptomatic and supportive.
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Desmopressin acetate (DDAVP) has been shown to shorten bleeding time in some, but not all, patients with BSS. It may be useful for minor bleeding episodes.

More recently, recombinant activated factor VII has been used in patients with congenital platelet disorders including BSS. Work with the recombinant activated factor VII is under the direction of Dr. M. C. Poon and Dr. R d'Oiron of the Department of Medicine, University of Calgary and Foothills Hospital, Alberta, Canada. (mcpoon@ucalgary.ca).

More study is need to determine the safety and efficacy of these therapeutic agents.
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McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Entry Number; 231200: Last Edit Date; 10/2/2001.

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Bennett JC, Plum F. Eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:985

REVIEW ARTICLES
Balduini CL, Iolascon A, Savoia A. Inherited thrombocytopenias: from genes to therapy. Hematologica. 2002;87:860-80.

Nurden AT, Nurden P. Inherited defects of platelet function. Rev Clin Exp Hematol. 2001;5:314-34.

Clemetson KJ. Platelet glycoproteins and their role in disease. Transfus Clin Biol. 2001;8:155-62.

Monroe DM, Hoffman M, Allen GA, et al. The factor VII-platelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopenia. Semin Thromb hemost. 2000;26:373-77.

JOURNAL ARTICLES
Nurden AT, Combrie R, Claeyssens S, et al. Heterozygotes in the bernard-soulier syndrome do not necessarily have giant platelets or thrombocytopenia. Br J Haematol. 2003;120:716-17.

Kunishima S, Kamiya T, Saito H. Genetic abnormalities of Bernard-Soulier syndrome. Int J Hematol. 2002;76:319-27.

Nakagawa M, Okuno M, Okamoto N, et al. Bernard-Soulier syndrome associated with 22q11.2 microdeletion. Am J Med genet. 2001;99:286-88.

Toren A, Rozenfeld-Granot G, Rocca B, et al. Autosomal-dominant giant platelet syndromes: a hint of the same genetic effect as in Fechtner syndrome owing to a similar genetic linkage ro chromosome 22q11-13. Blood. 2000;96:3447-51.

Poon MC, d’Oiron R. Recombinant activated factor VII (NovoSeven) treatment of platelet-related bleeding disorders. International Registry on Recombinant Factor VIIa and Congenital Platelet Disorders Group. Blood Cloagul Fibrinolysis. 200;11 (Suppl 1):S55-68.

Hayashi T, Suzuki K. Molecular pathogenesis of Bernard-Soulier syndrome. Semin Thrommb Hemost. 2000;26:53-59.

Noda M, Fujimura K, Takafuta T, et al. Heterogeneous expression of glycoprotein Ib, IX and V in platelets from two patients with Bernard-Soulier syndrome caused by different genetic abnormalities. Thromb Haemost. 1995;74:1411-15

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eMedicine-Bernard-Soulier Syndrome: Article by John D Geil, MD

http://www.emedicine.com/ped/topic230.htm