Cases reported "Bernard-Soulier Syndrome"

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1/85. Molecular characterization of two mutations in platelet glycoprotein (GP) Ib alpha in two Finnish bernard-soulier syndrome families.

    bernard-soulier syndrome (BSS) is a rare hereditary bleeding disorder and macrothrombocytopenia which is caused by a defect in the platelet glycoprotein Ib/IX/V (GP Ib/IX/V) complex, the receptor for von willebrand factor and thrombin. Here we report the molecular basis of the classical form of BSS in two unrelated Finnish patients, both with a life-long history of severe bleeding. flow cytometry and immunoblotting showed no expression of GP Ib/IX, GP Ib alpha, GP Ib beta or GP IX (less than 10%) in the patients' platelets. No expression of GP V (< 10%) was observed in propositus 1, but a residual amount was found in propositus 2 (24%). dna sequencing analysis revealed that propositus 1 was compound heterozygous for a two-base-pair deletion at Tyr505(TAT) and a point mutation Leu129(CTC)Pro(CCC) in the GP Ib alpha gene. Propositus 2 was homozygous for the Tyr505(TAT) deletion. The nine relatives who were heterozygous for either of the mutations also had low levels of GP Ib alpha (74-90%). Hence, Bernard-Soulier patients homozygous or compound heterozygous for Tyr505(TAT) are severely affected. Interestingly, both mutations have independently been found in three other families in previous reports, suggesting their ancient age or mutational 'hot spot'. ( info)

2/85. The critical interaction of glycoprotein (GP) IBbeta with GPIX-a genetic cause of bernard-soulier syndrome.

    bernard-soulier syndrome is an uncommon bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP)Ib/IX complex. The complex is composed of four subunits, GPIbalpha, GPIbbeta, GPIX, and GPV. Here we describe the molecular basis of a novel bernard-soulier syndrome variant in a patient in whom GPIbalpha and GPIX were undetectable on the platelet surface. dna sequence analysis showed normal sequence for GPIbalpha, GPIX, and GPV. The GPIbbeta gene has been mapped to the 22q11.2 region of chromosome 22 which was deleted from one chromosome of this patient. There was a single nucleotide deletion within the codon for Ala 80 in GPIbbeta within the other allele. This mutation causes a translational frame shift that encodes for 86 altered amino acids and predicts a premature stop 15 amino acids short of the length of the wild-type protein. Transient coexpression of the mutant GPIbbeta in 293T cells with wild-type GPIbalpha and GPIX resulted in the surface expression of GPIbalpha, but the absence of GPIX. Moreover, when a plasmid encoding the wild-type GPIbbeta was transiently transfected into Chinese hamster ovary cells stably expressing GPalpha, which retain the capacity to reexpress GPIX, there was a significant increase in the surface expression of GPIX. In contrast, when the mutant GPIbbeta was transiently transfected into these cells, GPIX was not reexpressed on the plasma surface. Thus, a deletion of one copy of GPIbbeta and a single nucleotide deletion in the codon for Ala 80 within the remaining GPIbbeta allele causes the Bernard-Soulier phenotype through an interaction of GPIbbeta with GPIX resulting in the absence of GPIbalpha on the plasma membrane. The interaction of GPIbbeta with GPIX is essential for the functional expression of GPIbalpha. ( info)

3/85. Compound heterozygosity (554-589 del, C515-T transition) in the platelet glycoprotein Ib alpha gene in a patient with a severe bleeding tendency.

    Giant platelets in the blood smear, absent in vitro platelet agglutination in response to ristocetin, and normal aggregation, ATP secretion and thromboxane b2 formation were found in a young patient with a life-long bleeding tendency. ristocetin-induced von willebrand factor binding to her platelets was less than 10% of normal. Flow cytometric analysis with monoclonal antibodies LJ-Ib-1, LJ-Ib-10, and LJ-P3 was consistent with the latter finding. SDS-PAGE analysis of solubilized platelets showed a marked reduction of the platelet glycoprotein (GP) Ibalpha. Genetic characterisation demonstrated that the patient and her father were heterozygous for a deletion of 36 nucleotides (positions 554-589) leading to a mutant GPIalpha (deletion of aminoacids from residue 169 to 180 and a Glu --> Lys substitution at residue 181). In addition, a C --> T transition at nucleotide 515 in the other allele of the GPIbalpha gene was found in the patient and in her mother that results in the substitution of alanine for valine in codon 156 (Bernard-Soulier type Bolzano). These variations occurred within the VI and VII leucine-rich repeats. The novel variant of bernard-soulier syndrome identified further suggests that the integrity of leucine-rich repeats is important for normal function of the GP Ib-IX-V receptor complex. ( info)

4/85. Giant platelet disorders in African-American children misdiagnosed as idiopathic thrombocytopenic purpura.

    A retrospective chart review of six African-American children with a diagnosis of macrothrombocytopenias (MTCP) was performed to evaluate the accuracy of their diagnosis. The following was diagnosed in the six children with MTCP: Fechtner syndrome (two children), Sebastian syndrome (one child), and unnamed MTCP (three children). In five families, chronic idiopathic thrombocytopenic purpura (ITP) was diagnosed in the propositus, which resulted in therapy using steroids, intravenous immunoglobulin (IVIG), and in one case splenectomy. Bleeding symptoms were generally mild. All six patients had thrombocytopenia ranging from 10 to 125 x 10(9)/L with mean platelet volume of 8 to 20 fL. Bleeding times were abnormal in two of three patients, and platelet aggregation was abnormal in three of four patients tested. bone marrow aspirates were reported as increased megakaryocytes in the three patients on whom the procedure was performed. Ultrastructural morphology of platelets and leukocytes was performed in all six patients demonstrating giant platelets in all six patients and leukocyte inclusions in three patients. Differentiating MTCP from the more common ITP can be difficult but important in avoiding unnecessary diagnostic studies and potentially harmful therapy associated with ITP. ( info)

5/85. Antepartum diagnosis of fetal intracranial hemorrhage due to maternal bernard-soulier syndrome.

    BACKGROUND: bernard-soulier syndrome, a lack of glycoprotein IB/IX, is a rare autosomal recessive bleeding disorder characterized by platelet dysfunction. women with bernard-soulier syndrome are at risk of being immunized against glycoprotein IB/IX, leading to severe isoimmune neonatal thrombocytopenia. CASE: A 26-year-old Japanese woman, gravida 1, para 0, with bernard-soulier syndrome presented at 35 weeks' gestation with changes in fetal heart rate patterns and ultrasonographic findings that strongly suggested fetal intracranial hemorrhage. Management was by cesarean hysterectomy and bilateral salpingo-oophorectomy at 36 weeks, but the neonate died 6 hours after birth. CONCLUSION: Maternal immunization to glycoprotein IB/IX during pregnancy can cause severe fetal thrombocytopenia and massive intracranial bleeding. ( info)

6/85. Vestibular closure with a silastic obturator--an alternative to Young's procedure in bleeding diathesis.

    epistaxis is a common and difficult problem to manage in patients with bleeding disorders. We present a case of recurrent epistaxis in a patient with bernard-soulier syndrome (a platelet disorder) and describe a non-invasive but effective method of closing the nasal vestibule using a silastic obturator thus preventing the drying effects of airflow on the nasal mucosa which may precipitate epistaxis in patients with a bleeding diathesis. ( info)

7/85. Cys97-->Tyr mutation in the glycoprotein IX gene associated with Bernard-Soulier syndrome.

    bernard-soulier syndrome (BSS) is an autosomal recessive bleeding disorder due to quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von willebrand factor. We describe here the genetic basis of the disorder in a patient with BSS. Flow cytometric analysis of the patient's platelets showed a greatly reduced GPIbalpha and completely absent GPIX surface expression. Immunoblot analysis disclosed greatly reduced GPIbalpha and residual amounts of GPIbbeta and GPIX in the platelets. dna sequencing analysis revealed the patient to be homozygous for a novel missense mutation in the GPIX gene that converts Cys (TGT) to Tyr (TAT) at residue 97. Transient transfection studies confirmed that mutant GPIX was not expressed on the transfected cells, showing that the mutation was responsible for the BSS phenotype observed in the patient. ( info)

8/85. Acquired bernard-soulier syndrome: a case with necrotizing vasculitis and thrombosis.

    We describe a patient with positive antinuclear antibodies, polyclonal gammopathy and high level of circulating immunocomplexes, resulting in vascular purpura. In addition, the patient had a slightly prolonged bleeding time and an isolated defect of ristocetin-induced platelet aggregation (RIPA) in platelet-rich plasma (PRP). The patient's plasma also inhibited RIPA in normal PRP and in normal platelet suspension. The activity and multimeric structure of plasmatic von willebrand factor showed no alteration. We could demonstrate an autoantibody against platelet membrane glycoprotein (GP) Ib, using an ELISA-type assay. These data suggest an acquired bernard-soulier syndrome. We suggest that the patient had an immunocomplex-mediated leukocytoclastic vasculitis accompanied by production of antinuclear autoantibodies as well as the presence of an autoantibody against GPIb. The titer of the anti-GPIb antibody, however, was too low to induce significant platelet-type bleeding tendency, only laboratory alterations were found. Moreover, in a later stage of her disease, she developed a severe necrotizing vasculitis which was followed by a deep venous thrombosis. ( info)

9/85. Surface expression of glycoprotein ib alpha is dependent on glycoprotein ib beta: evidence from a novel mutation causing bernard-soulier syndrome.

    bernard-soulier syndrome is a rare bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP) Ib-IX-V complex. The complex, which serves as a platelet receptor for von willebrand factor, is composed of 4 subunits: GPIb alpha, GPIb beta, GPIX, and GPV. We here describe the molecular basis of a novel form of bernard-soulier syndrome in a patient in whom the components of the GPIb-IX-V complex were undetectable on the platelet surface. Although confocal imaging confirmed that GPIb alpha was not present on the platelet surface, GPIb alpha was readily detectable in the patient's platelets. Moreover, immunoprecipitation of plasma with specific monoclonal antibodies identified circulating, soluble GPIb alpha. dna-sequence analysis revealed normal sequences for GPIb alpha and GPIX. There was a G to A substitution at position 159 of the gene encoding GPIb beta, resulting in a premature termination of translation at amino acid 21. Studies of transient coexpression of this mutant, W21stop-GPIb beta, together with wild-type GPIbalpha and GPIX, demonstrated a failure of GPIX expression on the surface of HEK 293T cells. Similar results were obtained with Chinese hamster ovary alpha IX cells, a stable cell line expressing GPIbalpha that retains the capacity to re-express GPIX. Thus, we found that GPIbbeta affects the surface expression of the GPIb-IX complex by failing to support the insertion of GPIb alpha and GPIX into the platelet membrane. (blood. 2000;96:532-539) ( info)

10/85. Homozygous Pro74-->Arg mutation in the platelet glycoprotein Ibbeta gene associated with bernard-soulier syndrome.

    bernard-soulier syndrome (BSS) is an autosomal recessive bleeding disorder due to quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von willebrand factor. This complex is composed of four subunits, GPIbalpha, GPIbbeta, GPIX and GPV. We describe here the genetic basis of the disorder in a patient with BSS. Flow cytometric analysis of the patient's platelets showed greatly reduced GPIbalpha and GPIX surface expression. Immunoblot analysis disclosed absence of GPIbalpha, GPIbbeta and GPIX in the platelets. dna sequencing analysis revealed a novel missense mutation in the GPIbbeta gene that converts Pro (CCG) to Arg (CGG) at residue 74. Homozygosity of the mutation was confirmed by allele-specific restriction analysis, chromosome 22 microsatellite analysis and quantitative Southern blotting. The mutant GPIbbeta was normally transcribed. Transient transfection studies confirmed that mutant GPIbbeta impairs surface expression of GPIb/IX, showing that the mutation is responsible for a BSS phenotype observed in the patient. ( info)
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