Coinheritance of Severe von Willebrand Disease With Glanzmann Thrombasthenia

Ahmad, Firdos; Kannan, Meganathan; Kishor, Kamal; Saxena, Renu

doi:10.1177/1076029609360527

Cited by 3 publications

(3 citation statements)

References 12 publications

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“…Glanzmann's thrombasthenia and type 2N VWD Pontara et al 403 between Glanzmann's thrombasthenia and VWD has already been reported, taking into account that VWD is the most common inherited bleeding disorder [18,19], which involved quantitative VWF defects (type 1 and type 3 VWD).…”

Section: Discussionmentioning

confidence: 89%

Spontaneous hemarthrosis in combined Glanzmann thrombasthenia and type 2N von Willebrand disease

Pontara¹,

Gresele²,

Cattini³

et al. 2014

Blood Coagulation &Amp; Fibrinolysis

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Glanzmann thrombasthenia is a rare autosomal recessive inherited bleeding disorder characterized by the lack of platelet aggregation, caused by deficiencies and/or abnormalities of platelet GPIIb-IIIa receptor. We report a case of Glanzmann thrombasthenia combined with type 2N von Willebrand disease (VWD), a variant characterized by an impaired capacity of FVIII to bind von Willebrand factor (VWF), which results in an autosomally transmitted reduction in circulating FVIII levels. Glanzmann thrombasthenia stems from compound T1214C and G1234A mutations in the ITGA2B gene; the type 2N VWD is due to a heterozygous G2561A mutation in the VWF gene (R854Q). The haemostatic phenotype of a 48-year-old female patient was unusually characterized by a severe chronic arthropathy with loss of cartilage and the presence of subchondrial cysts involving both ankles. The arthropathy was quantified with the compatible MRI scoring system (currently used to assess arthropathy in haemophilia), reaching almost the highest score. These haemorrhagic complications are very rare in Glanzmann thrombasthenia and resemble those seen in severe haemophilia; for such, a reason we decided to explore the patient's FVIII and VWF parameters. Our findings suggest that the type 2N R854Q mutation, which is normally asymptomatic at the heterozygous level, may be expressed in the presence of a combined impairment of primary haemostasis.

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Section: Discussionmentioning

confidence: 89%

Spontaneous hemarthrosis in combined Glanzmann thrombasthenia and type 2N von Willebrand disease

Pontara¹,

Gresele²,

Cattini³

et al. 2014

Blood Coagulation &Amp; Fibrinolysis

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“…For instance, rare coinheritance of GT with other bleeding disorders has been reported. 62 To ensure only families with true lack of segregation ($2 affected family members with at least 1 affected individual not carrying the variant of interest) are included, the PD-EP specifies that all affected family members must be well documented as having GT based on both bleeding phenotype and appropriate laboratory values (meeting the PP4_moderate criterion).…”

Section: Segregation Datamentioning

confidence: 99%

Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel

et al. 2021

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Accurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to 5 rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.

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“…However, excluding the forms for which a candidate gene is known, the identification of new genetic defects underlying an IPFD is challenging and made particularly difficult by the complexity of the mechanisms regulating platelet activation, with many proteins not yet known to be involved in platelet function. Moreover, platelet disorders are heterogeneous and sometimes are coinherited with other genetic defects, such as the association of VWD and Glanzmann thrombasthenia, 18,52 or VWD and heterozygous mutations in platelet proteins (P2Y 12 , TP, and GPVI). 19 Finally, complex genetic conditions such as compound heterozygosity, large chromosome deletions (del11q23-ter in Paris Trousseau syndrome), and compound inheritance of a null allele and one point mutation (the 1q21.1 deletion associated with a point mutation in RBM8A described in thrombocytopenia absent radii 53 ), render the unraveling of an underlying genetic defect particularly complex.…”

Section: Genetic Testingmentioning

confidence: 99%

Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation

Gresele

Bury

Falcinelli

2016

Semin Thromb Hemost

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Inherited platelet function disorders (IPFDs) manifest with mucocutaneous bleeding and are frequently difficult to diagnose due to their heterogeneity, the complexity of the platelet activation pathways and a lack of standardization of the platelet function laboratory assays and of their use for this purpose. A rational diagnostic approach to IPFDs should follow an algorithm where clinical examination and a stepwise laboratory evaluation play a crucial role. A streamlined panel of laboratory tests, with consecutive steps of increasing level of complexity, allows the phenotypic characterization of most IPFDs. A first-line diagnosis of a significant fraction of the IPFD may be made also at nonspecialized centers by using relatively simple tests, including platelet count, peripheral blood smear, light transmission aggregometry, measurement of platelet granule content and release, and the expression of glycoproteins by flow cytometry. Some of the most complex, second- and third-step tests may be performed only in highly specialized laboratories. Genotyping, including the widespread application of next-generation sequencing, has enabled discovery in the last few years of several novel genes associated with platelet disorders and this method may eventually become a first-line diagnostic approach; however, a preliminary clinical and laboratory phenotypic characterization nowadays still remains crucial for diagnosis of IPFDs.

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Coinheritance of Severe von Willebrand Disease With Glanzmann Thrombasthenia

Cited by 3 publications

References 12 publications

Spontaneous hemarthrosis in combined Glanzmann thrombasthenia and type 2N von Willebrand disease

Spontaneous hemarthrosis in combined Glanzmann thrombasthenia and type 2N von Willebrand disease

Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel

Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation

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