RESUMO
Bernard-Soulier syndrome (BSS) is caused by defects in GP1BA, GP1BB, or GP9 genes. Patients with 22q11.2 deletion syndrome (22q11.2DS) are obligate carriers of BSS because GP1BB resides on chromosome 22q11.2. A 15-month-old girl without bleeding symptoms had giant platelets and thrombocytopenia. Physical findings and macrothrombocytopenia suggested 22q11.2DS, which was confirmed by fluorescence in situ hybridization. Flow cytometry showed decreased GPIbα on the platelets. Gene panel testing revealed a novel variant in GP1BB, p.(Val169_Leu172del). These findings confirmed that the patient had BSS. This case suggests that any patient with 22q11.2DS and macrothrombocytopenia should be further tested for BSS.
Assuntos
Síndrome de Bernard-Soulier , Complexo Glicoproteico GPIb-IX de Plaquetas , Humanos , Síndrome de Bernard-Soulier/genética , Síndrome de Bernard-Soulier/diagnóstico , Feminino , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Lactente , Cromossomos Humanos Par 22/genética , Plaquetas/metabolismo , Plaquetas/patologia , Trombocitopenia/genética , Trombocitopenia/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/complicações , Deleção CromossômicaRESUMO
BACKGROUND: Bernard-Soulier syndrome (BSS) is a rare inherited macrothrombocytopenia, usually autosomal recessive, which is characterized by prolonged bleeding, thrombocytopenia, and abnormally large platelets. METHODS: For more than 6 years, we misdiagnosed a patient with BSS without an obvious bleeding tendency as having idiopathic thrombocytopenia purpura (ITP), prior to obtaining a genetic analysis. On admission, routine hematology showed a platelet count of 30 × 109/L and mean platelet volume (MPV) of 14.0 fL. RESULTS: Whole-exome sequencing revealed two likely pathogenic heterozygous mutations (c.95_101del and c.1012del) in GP1BA. Flow cytometry analysis of platelet membrane glycoproteins indicated that the expression of GP1b was 0.28% of the normal level. Platelet aggregation tests indicated that platelet aggregation was inhibited by ristocetin- (1.7%), ADP- (14.5%), and arachidonic acid- (5.6%) induced platelet aggregation. A literature review identified reports on 53 mutations in the GP1BA gene in 253 patients, 29 mutations in the GP1BB gene in 90 patients, and 32 mutations in the GP9 gene in 114 patients. CONCLUSION: This case report describes two novel gene mutation sites that have not been reported previously, enriching understanding of the GP1BA mutation spectrum.
Assuntos
Síndrome de Bernard-Soulier , Trombocitopenia , Humanos , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Contagem de Plaquetas , Citometria de Fluxo , MutaçãoRESUMO
Bernard-Soulier syndrome (BSS), also known as hemorrhagiparous thrombocytic dystrophy (OMIA 002207-9615), is a rare defect in platelet function recognized in both dogs and humans. It is caused by a deficiency in glycoprotein 1b-IX-V, the platelet surface protein which acts as a receptor for the von Willebrand factor. The characteristic features of BSS in humans and dogs include macrothrombocytes and mild-to-moderate thrombocytopenia with a bleeding tendency. This condition has previously been reported in European Cocker Spaniel dogs; however, the results of platelet function tests in these animals have not been reported. This case report describes a European Cocker Spaniel dog with spontaneously occurring Bernard-Soulier syndrome and the results of point-of-care platelet function tests, including a prolonged buccal mucosal bleeding time (>8 min), prolongation (>300 s) of PFA-200 COL/ADP, COL/EPI, and P2Y closure times, and reduced aggregation (15%-48%) with Plateletworks ADP, but with normal aggregation (92%) with Plateletworks AA. This is the first description of the results of platelet function tests in canine Bernard-Soulier syndrome.
Assuntos
Síndrome de Bernard-Soulier , Doenças do Cão , Transtornos Hemorrágicos , Humanos , Cães , Animais , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/veterinária , Síndrome de Bernard-Soulier/metabolismo , Sistemas Automatizados de Assistência Junto ao Leito , Plaquetas/metabolismo , Hemostasia , Complexo Glicoproteico GPIb-IX de Plaquetas , Transtornos Hemorrágicos/veterinária , Doenças do Cão/diagnóstico , Doenças do Cão/metabolismoRESUMO
BACKGROUND: Bernard Soulier Syndrome (BSS) is a rare autosomal recessive disorder due to deficiency or dysfunction of the glycoprotein GPIb-V-IX complex on the platelet surface. It is also known as hemorrhagiparous thrombocytic dystrophy or congenital hemorrhagiparous thrombocytic dystrophy. The patient usually presents with severe and prolonged bleeding along with characteristics of giant blood platelets and low platelet counts. Manifestations of BSS include epistaxis, gum bleeding, purpuric rashes, menorrhagia, rarely melena, and hematemesis. On the other hand, immune thrombocytopenic purpura (ITP) is an acquired autoimmune disorder in which there is accelerated platelet destruction and reduced platelet production. Isolated thrombocytopenia without fever, lymphadenopathy, and organomegaly usually lead to the diagnosis of immune thrombocytopenia. CASE PRESENTATION: A 20 years old female presented with complaints of recurrent episodes of epistaxis since childhood and menorrhagia during menarche. She was misdiagnosed as ITP elsewhere. Later, based on thorough clinical examination and investigation, the diagnosis was confirmed as BSS. CONCLUSION: BSS should always be taken in the differential diagnosis of ITP, especially when persistent, refractory, and treated unsuccessfully with steroids or splenectomy.
Assuntos
Síndrome de Bernard-Soulier , Menorragia , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Feminino , Criança , Adulto Jovem , Adulto , Síndrome de Bernard-Soulier/diagnóstico , Púrpura Trombocitopênica Idiopática/diagnóstico , Epistaxe , Complexo Glicoproteico GPIb-IX de Plaquetas , PlaquetasRESUMO
OBJECTIVE: Bernard-Soulier syndrome (BSS) is one of the rare inherited platelet disorders that is characterized by macrothrombocytopenia and adhesion abnormality due to the absence or malfunctioning of the membrane GPIb-IX-V complex. There is no high-quality evidence on obstetric management of BSS owing to its rarity. Here we report an uncomplicated delivery of an adolescent with BSS and review the literature on the topic of BSS and pregnancy. METHODS: PUBMED, EMBASE, COCHRANE, and Google Scholar databases were searched up to April 2022 without language and year restriction using the terms "Bernard Soulier" and "Pregnancy". The primary objectives were to evaluate maternal and fetal outcomes. The secondary objectives were to analyze pregnancy complications, gestational age at delivery, mode of delivery, administered prophylaxis, treatment approaches, duration of postpartum hospitalization, and the postpartum requirement of blood and blood product. RESULTS: The patient was a 19-year-old and 39-week pregnant woman who was diagnosed with BSS at the age of 10 by flow cytometry and genetic analysis. Single donor platelet transfusions and oral tranexamic acid were administered as prophylaxis at the peripartum period. She was delivered by cesarean section due to failure of labor. The postpartum period was uneventful for both mother and neonate. In the literature review, postpartum hemorrhage (PPH) was found in 52.9% (27/51) of deliveries. Late PPH occurred more frequently than early PPH (35.3 and 31.4%, respectively). 49% (25/51) of pregnancies had severe thrombocytopenia, and antepartum hemorrhage was observed in 11.8% (6/51) of those. The platelet count was in close relation to antenatal complications. 64.7% (33/51) of the patients were delivered via cesarean section. PPH and late PPH were found to be more common in those who delivered vaginally compared to those who delivered by caesarean section. It was observed that PPH was less common in women who were given prophylaxis in the peripartum period. CONCLUSION: BSS is an inherited macro-thrombocytopathy that may cause adverse maternal and neonatal outcomes. The optimal mode and timing of delivery remain unclear. A multidisciplinary approach with prophylaxis at the peripartum period should be applied.
Assuntos
Síndrome de Bernard-Soulier , Hemorragia Pós-Parto , Complicações na Gravidez , Gravidez , Recém-Nascido , Adolescente , Feminino , Humanos , Adulto Jovem , Adulto , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/terapia , Síndrome de Bernard-Soulier/complicações , Cesárea/efeitos adversos , ObstetraRESUMO
Diagnosis of inherited platelet glycoprotein disorders is based on specific laboratory techniques such as aggregometry and flow cytometry. Flowcytometry is a powerful method, but equivocal results are produced in some cases. New cluster of differentiation markers could resolve the diagnostic dilemmas. Abnormal expression of CD9 in Bernard-Soulier syndrome (BSS) is recently reported. We aimed to determine the diagnostic significance of CD9 expression in a cohort of Iranian patients with inherited platelet glycoprotein defects. Twelve BSS, 21 Glanzmann thrombasthenia and 16 healthy controls were included in the present study. Flowcytometric diagnosis of BSS and Glanzmann thrombasthenia was made by analysis of CD41/61 and CD42a/42b CD markers. Moreover, phycoerythrin-labelled anti CD9 was examined in patients and healthy controls. The mean fluorescence intensity (MFI) of CD9 among the three groups was compared using suitable statistical methods and a P value of less than 0.05 considered statistically significant. Mean MFI of CD9 was 990.0 in BSS patients versus 421.2 and 317.3 in individuals with Glanzmann thrombasthenia and healthy controls, respectively (Pâ<â0.05). Between the two-group comparison of means by the Mann-Whitney test revealed a P value of less than 0.001 for BSS group versus GT (2.4-fold) and BSS versus healthy controls (2.9-fold). CD9 molecule also expressed differently in patients with Glanzmann thrombasthenia in comparison with healthy controls (Pâ<â0.001), although with a less magnitude (1.3-fold). According to our findings, CD9 is a potential biomarker for laboratory diagnosis of inherited glycoprotein defects, especially to elucidate the ambiguous results in BSS cases.
Assuntos
Síndrome de Bernard-Soulier , Transtornos Plaquetários , Trombastenia , Síndrome de Bernard-Soulier/diagnóstico , Biomarcadores/metabolismo , Plaquetas/metabolismo , Humanos , Irã (Geográfico) , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Tetraspanina 29/metabolismo , Trombastenia/diagnósticoRESUMO
Bernard-Soulier syndrome (BSS) is a rare inherited disorder characterized by unusually large platelets, low platelet count, and prolonged bleeding time. BSS is usually inherited in an autosomal recessive (AR) mode of inheritance due to a deficiency of the GPIb-IX-V complex also known as the von Willebrand factor (VWF) receptor. We investigated a family with macrothrombocytopenia, a mild bleeding tendency, slightly lowered platelet aggregation tests, and suspected autosomal dominant (AD) inheritance. We have detected a heterozygous GP1BA likely pathogenic variant, causing monoallelic BSS. A germline GP1BA gene variant (NM_000173:c.98G > A:p.C33Y), segregating with the macrothrombocytopenia, was detected by whole-exome sequencing. In silico analysis of the protein structure of the novel GPIbα variant revealed a potential structural defect, which could impact proper protein folding and subsequent binding to VWF. Flow cytometry, immunoblot, and electron microscopy demonstrated further differences between p.C33Y GP1BA carriers and healthy controls. Here, we provide a detailed insight into its clinical presentation and phenotype. Moreover, the here described case first presents an mBSS patient with two previous ischemic strokes.
Assuntos
Alelos , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Predisposição Genética para Doença , Variação Genética , Fenótipo , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Síndrome de Bernard-Soulier/sangue , Plaquetas/metabolismo , Plaquetas/ultraestrutura , República Tcheca , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Imunofenotipagem , Masculino , Linhagem , Contagem de Plaquetas , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Trombocitopenia/sangue , Trombocitopenia/diagnósticoRESUMO
Immune thrombocytopenia (ITP) is an acquired bleeding disorder, for which no specific diagnostic test exists. Inherited thrombocytopenia (IT) can mimic ITP and lead to unappropriated management with significant morbidity. Here, in small cohorts of these two disorders, we explored whether platelet sialylation and platelet activation could allow to discriminate the two conditions. We also aimed to confirm the value of immature platelet counts in this discrimination. Platelet sialylation and the expression level of P-selectin were assessed by multiparameter flow cytometry. Immature platelets were estimated on a Sysmex XN 9000 analyzer. No significant difference in platelet sialylation was observed between ITP and IT. Contrarily, platelet activation was significantly higher in ITP patients (p = 0.008). The immature platelet fraction, as previously demonstrated, was significantly lower in the ITP group compared to the IT group (p = 0.014). That statistical significance was achieved in this small pilot study suggests that the two easily available assays of immature platelet count and P-selectin expression could help physicians to reach the proper diagnosis in complex cases of thrombocytopenia.
Assuntos
Plaquetas/química , Ativação Plaquetária , Ácidos Siálicos/sangue , Trombocitopenia/sangue , Adulto , Idoso , Área Sob a Curva , Síndrome de Bernard-Soulier/sangue , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Senescência Celular , Diagnóstico Diferencial , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Projetos Piloto , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Curva ROC , Sensibilidade e Especificidade , Trombocitopenia/diagnóstico , Trombocitopenia/genéticaRESUMO
BACKGROUND: The classic Bernard-Soulier syndrome (BSS) is a rare inherited thrombocytopenia (IT) associated with severe thrombocytopenia, giant platelets, and bleeding tendency caused by homozygous or compound heterozygous variants in GP1BA, GP1BB, or GP9. Monoallelic BSS (mBSS) associated with mild asymptomatic macrothrombocytopenia caused by heterozygous variants in GP1BA or GP1BB may be a frequent cause of mild IT. OBJECTIVE: We aimed to examine the frequency of mBSS in a consecutive cohort of patients with IT and to characterize the geno- and phenotype of mBSS probands and their family members. Additionally, we set out to examine if thrombopoietin (TPO) levels differ in mBSS patients. PATIENTS/METHODS: We screened 106 patients suspected of IT using whole exome- or whole genome sequencing and performed co-segregation analyses of mBSS families. All probands and family members were phenotypically characterized. Founder mutation analysis was carried out by certifying that the probands were unrelated and the region around the variant was shared by all patients. TPO was measured by solid phase sandwich ELISA. RESULTS: We diagnosed 14 patients (13%) with mBSS associated with heterozygous variants in GP1BA and GP1BB. Six unrelated probands carried a heterozygous variant in GP1BA (c.58T>G, p.Cys20Gly) and shared a 2.0 Mb region on chromosome 17, confirming that it is a founder variant. No discrepancy of TPO levels between mBSS patients and wild-type family members (P > .05) were identified. CONCLUSION: We conclude that the most frequent form of IT in Denmark is mBSS caused by the Copenhagen founder variant.
Assuntos
Síndrome de Bernard-Soulier , Trombocitopenia , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Dinamarca , Homozigoto , Humanos , Linhagem , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Trombocitopenia/diagnóstico , Trombocitopenia/genéticaRESUMO
Bernard Soulier syndrome is a rare, congenital platelet bleeding disorder, with autosomal recessive inheritance. It is characterised by macrothrombocytopenia and platelet dysfunction, leading to mucocutaneous bleeding noted in early childhood. This entity poses an important diagnostic challenge, and blood smear and DNA sequencing are paramount for the correct diagnosis. Differential diagnosis includes May-Hegglin anomaly, Glanzmann Thrombasthenia and von Willebrand disease; it is also often misdiagnosed as idiopathic thrombocytopenic purpura. We report a 68-year-old man diagnosed with von Willebrand disease for three decades, admitted with gastrointestinal bleeding, anaemia and severe thrombocytopenia. Replacement with von Willebrand factor did not stop the haemorrhage, suggesting another aetiology for the bleeding disorder. Corticosteroids and intravenous immune globulin were also ineffective. Genetic sequencing showed a homozygous mutation in GP1BA gene, thus establishing the correct diagnosis.
Assuntos
Síndrome de Bernard-Soulier , Trombocitopenia , Doenças de von Willebrand , Idoso , Síndrome de Bernard-Soulier/diagnóstico , Pré-Escolar , Erros de Diagnóstico , Humanos , Masculino , Complexo Glicoproteico GPIb-IX de Plaquetas , Trombocitopenia/diagnósticoAssuntos
Síndrome de Bernard-Soulier , Mutação de Sentido Incorreto , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Púrpura Trombocitopênica Idiopática , Corticosteroides/administração & dosagem , Substituição de Aminoácidos , Benzoatos/administração & dosagem , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Síndrome de Bernard-Soulier/patologia , Síndrome de Bernard-Soulier/terapia , Criança , Diagnóstico Diferencial , Humanos , Hidrazinas/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Transfusão de Plaquetas , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/patologia , Púrpura Trombocitopênica Idiopática/terapia , Pirazóis/administração & dosagem , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Trombopoetina/administração & dosagemRESUMO
Bernard-Soulier syndrome (BSS) is an extremely rare autosomal recessive bleeding disorder clinically characterized by macrothrombocytopenia and a mucocutaneous bleeding tendency. A 1-year-old Chinese patient who was born to consanguineous parents was diagnosed with early onset of BSS. Gene sequencing and bioinformatics analysis were conducted. We identified a novel homozygous missense mutation (c.790T>C) in the GP1BAgene that causes an amino acid residue substitution of a cysteine with an arginine that might have a deleterious effect on the protein function as predicted by bioinformatics analysis. If a patient has clinical manifestations that include recurrent mucocutaneous bleeding, a mean platelet volume and platelet-large cell ratio above normal levels, and giant platelets on a peripheral smear and has consanguineous parents, a diagnosis of BSS can be suspected. In these situations, gene sequencing for mutations in the GPIb-IX-V complex is necessary.
Assuntos
Síndrome de Bernard-Soulier/diagnóstico , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Sequência de Bases , Síndrome de Bernard-Soulier/complicações , Síndrome de Bernard-Soulier/genética , Plaquetas/citologia , Plaquetas/metabolismo , Éxons , Hemorragia/etiologia , Homozigoto , Humanos , Lactente , Masculino , Mutação de Sentido IncorretoRESUMO
: Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder caused by a defective function of glycoprotein (GP) Ib-V-IX complex. Among the genes encoding the 4 receptor subunits (GPIbα, GPIbß, GPV and GPIX), the GPIbß gene is located on chromosomes 22q11.2. We report a case of a girl with BSS associated with clinical features of 22q11.2 deletion syndrome (22q11.2DS) with phenotypic spectrum of DiGeorge syndrome/velocardiofacial syndrome. She has a history of life-long bleeding tendency, tetralogy of Fallot, hypothyroidism, mild facial dysmorphic signs and macrothrombocytopenia. The BBS and 22q11.2DS association could be explained by the fact that the constitutional hemizygosity of 22q11.2 may unmask an autosomal recessive disorder caused by alterations of the nondeleted GPIbß allele. We suggest that all patients with 22q11.2DS and bleeding manifestations should be always tested for BSS.
Assuntos
Anormalidades Múltiplas/genética , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/patologia , Anormalidades Múltiplas/patologia , Síndrome de Bernard-Soulier/patologia , Deleção Cromossômica , Síndrome de DiGeorge/genética , Feminino , Hemorragia , Humanos , Complexo Glicoproteico GPIb-IX de Plaquetas , Adulto JovemRESUMO
The Bernard-Soulier syndrome also known as hemorrhagioparous thrombocytic dystrophy, is a rare autosomal recessive bleeding disorder. Macrothrombocytopenia and increased bleeding time are the two main features of this syndrome. There is a reduced adherence of giant platelets to the subendothelium due to a deficiency of glycoprotein GPIb-V-IX complex. Routine dental extraction in a patient with a bleeding disorder can lead to life-threatening complications and there are very few specific protocols for the same. Here, we present a case report describing haemostasis management during dental extraction in a 7-year-old female child, suffering from this syndrome. It was observed that the preoperative and postoperative human leucocyte antigen-matched platelet transfusion, systemic intraoperative tranexamic acid and minimally traumatic procedure improved bleeding control and management.
Assuntos
Síndrome de Bernard-Soulier/complicações , Hemostasia/efeitos dos fármacos , Extração Dentária/efeitos adversos , Administração Oral , Síndrome de Bernard-Soulier/diagnóstico , Plaquetas/patologia , Criança , Diagnóstico Diferencial , Feminino , Humanos , Transfusão de Plaquetas/métodos , Cuidados Pré-Operatórios , Ácido Tranexâmico/administração & dosagem , Ácido Tranexâmico/uso terapêutico , Resultado do TratamentoRESUMO
Essentials How thrombocytopenia relates to bleeding in 22q11 deletion syndrome (22q11DS) is not clear. Bleeding severity, platelet count and volume, and GPIBB were examined in patients with 22q11DS. Macrothrombocytopenia and bleeding typified imperfectly overlapping subsets of 22q11DS patients. GPIBB hemizygosity does not cause macrothrombocytopenia or bleeding in patients with 22q11DS. SUMMARY: Background and objectives Macrothrombocytopenia and bleeding are frequently associated with 22q11 deletion syndrome (22q11DS). GPIBB, which encodes the glycoprotein (GP) Ibß subunit of GPIb-IX-V, is commonly deleted in patients with 22q11DS. Absence of functional GPIb-IX-V causes Bernard-Soulier syndrome, which is a severe bleeding disorder characterized by macrothrombocytopenia. Patients with 22q11DS are often obligate hemizygotes for GPIBB, and those with only a pathogenically disrupted copy of GPIBB present with Bernard-Soulier syndrome. The objective of this study was to determine how GPIBB hemizygosity and sequence variation relate to macrothrombocytopenia and bleeding in patients with 22q11DS who do not have Bernard-Soulier syndrome. Patients/methods We thoroughly characterized bleeding severity, mean platelet volume, platelet count and GPIBB copy number and sequence in patients with 22q11DS. Results and conclusions Macrothrombocytopenia and mild bleeding were observed in incompletely overlapping subsets of patients, and GPIBB copy number and sequence variation did not correlate with either macrothrombocytopenia or bleeding in patients with 22q11DS. These findings indicate that GPIBB hemizygosity does not result in either macrothrombocytopenia or bleeding in these patients. Alternative genetic causes of macrothrombocytopenia, potential causes of acquired thrombocytopenia and bleeding and ways in which platelet size, platelet count and GPIBB sequence information can be used to aid in the diagnosis and management of patients with 22q11DS are discussed.
Assuntos
Síndrome da Deleção 22q11/genética , Síndrome de Bernard-Soulier/genética , Hemizigoto , Hemorragia/genética , Hemostasia/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Trombocitopenia/genética , Síndrome da Deleção 22q11/sangue , Síndrome da Deleção 22q11/diagnóstico , Adolescente , Síndrome de Bernard-Soulier/sangue , Síndrome de Bernard-Soulier/diagnóstico , Criança , Pré-Escolar , Feminino , Dosagem de Genes , Predisposição Genética para Doença , Hemorragia/sangue , Hemorragia/diagnóstico , Humanos , Masculino , Volume Plaquetário Médio , Repetições Minissatélites , Fenótipo , Contagem de Plaquetas , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sequência de DNA , Trombocitopenia/sangue , Trombocitopenia/diagnósticoRESUMO
Bernard-Soulier syndrome (BSS) is an autosomal recessive major thrombocytopathy, the symptoms of which are mainly marked by mucocutaneous bleeding. This rare disease, initially described in the 1970s, is the result of an abnormal formation of the glycoprotein complex Ib-IX-V (GP Ib-IX-V), a platelet receptor of von Willebrand factor. A large number of mutations, sometimes involving the GP9 gene, have been described as possibly responsible for the disease. We report here the case of a BSS patient who presented with persistent thrombocytopenia (31x109/L) and decreased surface expression of GPIb-IX-V on large platelets with anisocytosis. Thorough molecular analyses disclosed two previously unreported GP9 variants, respectively c.230T>A (p.Leu77Gln) and c.255C>A (p.Asn85Lys). Both are likely to modify the conformation of GP-IX interactions with other glycoproteins of the Ib-IX-V complex and thus proper expression of this complex on the membrane of platelets.
Assuntos
Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Variação Genética , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Alelos , Síndrome de Bernard-Soulier/sangue , Biomarcadores , Pré-Escolar , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Modelos Moleculares , Mutação , Fenótipo , Complexo Glicoproteico GPIb-IX de Plaquetas/química , Conformação Proteica , Análise de Sequência de DNA , Relação Estrutura-AtividadeRESUMO
The genes encoding the coagulation factors were characterized over two decades ago. Since then, significant progress has been made in the genetic diagnosis of the two commonest severe inherited bleeding disorders, haemophilia A and B. Experience with the genetic of inherited rare bleeding disorders and platelet disorders is less well advanced. Rare bleeding disorders are usually inherited as autosomal recessive disorders, while it is now clear that a number of the more common platelet function disorders are inherited as autosomal dominant traits. In both cases, DNA sequencing has been useful since most of these disorders are due to mutations located at the coding regions or splice sites of genes encoding the abnormal protein. However, in 5-10% of patients affected with severe clotting factor deficiencies, no genetic defect can be identified and until recently, the genetic characterization of inherited platelet disorders had been confined to the more prevalent conditions such as Glanzmann disease and Bernard-Soulier syndrome. In patients with no gene mutations identified, so far, the role of next-generation sequencing as well as of other new genomic technologies will very likely have increasing importance. However, such methods require extensive bioinformatics analysis that, in turn will require critical revision of our current diagnostic infrastructure.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/genética , Genômica , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Transtornos Plaquetários/diagnóstico , Transtornos Plaquetários/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Análise de Sequência de DNAAssuntos
Erros de Diagnóstico , Síndrome da Plaqueta Cinza/diagnóstico , Púrpura Trombocitopênica Idiopática/diagnóstico , Trombocitopenia/congênito , Adulto , Síndrome de Bernard-Soulier/diagnóstico , Diagnóstico Diferencial , Feminino , Síndrome da Plaqueta Cinza/diagnóstico por imagem , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Anamnese , Trombocitopenia/diagnósticoRESUMO
The main objective of this study is to investigate the utility of International Society on Thrombosis and Haemostasis-Bleeding Assessment Tool (ISTH-BAT) in comparison with the condensed form of Molecular and Clinical Markers for the Diagnosis and Management of type 1 and WHO BATs, in assessing bleeding in two well known and clinically significant platelet function defects. Thirty-eight patients previously diagnosed with Glanzmann's thrombasthenia and 10 with Bernard-Soulier syndrome (BSS) were analyzed. Bleeding scores were significantly higher than that of controls using both electronic bleeding questionnaire (eBQ) and ISTH-BAT with no significant difference between both tools. ISTH-BAT had a sensitivity, specificity, positive predictive value and negative predictive value of 100%, 76.2%, 0.9 and 1. This was closely similar to eBQ. Both ISTH-BAT and eBQ are efficient in BSS and Glanzmann's thrombasthenia. However, given the ISTH recommendation, ISTH-BAT should be adopted. Larger study including other platelet defects will enhance its utility and support the integration of bleeding scores with standardized laboratory testing to allow for a universal diagnostic approach to patients with suspected bleeding disorders.