Unique case of 19p13 syndrome with storage pool disease

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S104-S104
Author(s):  
S Liaquat ◽  
R Riley ◽  
G Massey ◽  
W T Gunning
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Disorder ◽  
Deletion Syndrome ◽  
Facial Dysmorphism ◽  
Chromosome 19 ◽  
Storage Pool ◽  
Platelet Function Disorders ◽  
Storage Pool Disease ◽  
Work Up

Abstract Introduction/Objective Microdeletion of a region of the short arm of chromosome 19 results in a very rare syndrome called 19p13.3 deletion syndrome, which manifest itself in developmental delay as well as structural abnormalities such as facial dysmorphism and macrocephaly. Methods/Case Report We present a case of 14-month-old patient, born at term and was large for her gestational age. She had dysmorphic facial features including posterior cleft palate for which, she required placement of G-tube. Post-delivery, she experienced respiratory distress as well as hypoglycemic episodes. Over the period of time, her mother also noticed occasional bleeding through her gums with teething. Genetic workup was performed, which revealed 2.4 Mb of microdeletion at chromosome 19 region p13.3, including deletion of PIAS4, MAP2K2, GNA11, TBXA2R, RAX2 genes. TBXA2R mutation is associated with bleeding disorder due to a defect in platelet aggregation. The mutation in TBXA2R can lead to platelet type 13 bleeding disorder. For this purpose, a platelet aggregation study was performed to evaluate platelet function disorders. However, the result of the platelet aggregation study was inconclusive as it showed decrease responses to all agonists including arachidonic acid, epinephrine, ADP, collagen and ristocetin. Further work-up by electron microscopy (EM) of platelets (PL) revealed a significant decrease of delta granules (DG) (0.89 DG/PL, normal 4-6 DG/PL), consistent with delta granule storage pool deficiency (δ-SPD). Other abnormalities observed by EM included occasional gray platelets, platelets with immature and/or decreased numbers of α-granules, and rare giant α-granules. Results (if a Case Study enter NA) NA Conclusion To the best of our knowledge, no other case of 19p13.3 microdeletion syndrome with δ-SPD and associated abnormalities in α-granules has previously been described in the literature. Although it is unclear if there is any relationship between δ-SPD and 19p13.3 deletion syndrome, further investigation is warranted.

Rab38 Expression in Platelet Dense Granule Storage Pool Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2112-2112
Author(s):  
Ivana Ninkovic ◽  
James G. White ◽  
Kenyatta W. Stephens ◽  
Artur Rangel-Fihlo ◽  
Francsisca C. Wu ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Flow Cytometric Analysis ◽  
Dense Granule ◽  
Bleeding Disorder ◽  
Coding Region ◽  
Platelet Dysfunction ◽  
Granule Formation ◽  
Storage Pool ◽  
Storage Pool Disease

Abstract Platelet dense granule storage pool disease (SPD) is a bleeding disorder characterized by a lack of normal platelet dense granule function, as evidenced by decreased platelet aggregation in response to ADP, epinephrine and collagen. Platelet SPD has been studied most extensively in humans and rodents with Hermansky-Pudlak syndrome (HPS), whose phenotype is a result of defects in granule trafficking, leading to oculocutanous albinism, lysosomal storage diseases, and platelet dysfunction. We have been characterizing the fawn-hooded hypertensive (FHH) rat, which has been previously shown to have a bleeding disorder consistent with a platelet SPD and some of the features of HPS. While the platelets in the FHH rat have normal alpha granules and lysosomes, they lack dense granules as assessed by transmission electron microscopy. Platelet flow cytometric analysis of GPIb and GPIIb indicated that the FHH platelets have normal surface expression of these adhesion proteins. The FHH rat has a mutation in the Rab38 gene at the ATG start site, which is associated with the bleeding disorder. Rab38 is part of a large family of GTPases, which are involved in granule formation and secretion. Western blotting of FHH tissues revealed that there is no expression of Rab38 protein. We have used confocal immunomicroscopy to assess Rab38 in platelet formation and function. In normal rat and human platelets, there was punctate expression of Rab38. There was no Rab38 staining detected in FHH platelets. In human megakaryocytic cell lines, Dami and HEL cells, there was punctate staining of Rab38 that was mainly in the periphery of the cells, with a variable amount of perinuclear staining. There was partial colocalization of Rab38 with serotonin and VWF, and with Lamp-3, a marker of lysosomes. The degree of colocalization varied between cells. There was no clear association of Rab38 with actin and tubulin in megakaryocytes. We also examined a cohort of patients with SPD, but not HPS, for mutations in Rab38. The entire coding region and intron-exon boundaries of the Rab38 gene were sequenced in 18 patient samples collected at Emory University for the CDC Women with Bleeding Disorders and Menorrhagia Study. Ten of the patients had platelet function defects documented by standard platelet aggregation studies, and eight had no identifiable platelet function defect. No mutations in Rab38 were detected. Whereas numerous known polymorphisms were identified and confirmed, there was no association of any of them with platelet function abnormalities. In conclusion, Rab38 is expressed in platelets and megakaryocytes and may interact with other granule proteins during megakaryocyte development. Failure to express Rab38 is associated with platelet dysfunction. Further studies are needed to determine its function in megakaryocytes and platelets, and to determine whether defects in Rab38 are a cause of platelet SPD in humans.

scholarly journals Further Evidence for a Deficient Storage Pool of Adenine Nucleotides in Platelets From Some Patients With Thrombocytopathia—"Storage Pool Disease"

Blood ◽  
1972 ◽  
Vol 39 (2) ◽  
pp. 197-209 ◽  
Author(s):  
Holm Holmsen ◽  
Harvey J. Weiss
Keyword(s):  
Platelet Aggregation ◽  
Adenine Nucleotides ◽  
Specific Radioactivity ◽  
Bleeding Disorder ◽  
The Other ◽  
Resting Cells ◽  
Release Reaction ◽  
Storage Pool ◽  
Storage Pool Disease ◽  
Specific Abnormality

Abstract The metalobism of adenine nucleotides in platelets was studied in one patient with thrombasthenia and in six patients whose bleeding disorder has been attributed to a defect in collagen-induced platelet aggregation associated with impaired release of platelet ADP (thrombocytopathia). In two of these patients no specific abnormality was found that might account for the defect in the release reaction (thrombocytopathia B). In the other four patients (thrombocytopathia A), significantly decreased amounts of platelet ATP and ADP and an increase in the ATP/ADP ratio were obtained. The specific radioactivity of both ATP and, more strikingly, ADP that was found after incubating their platelets with 3H-adenine was significantly greater than normal. This indicated that the patients’ platelets lacked the nonmetabolic pool of adenine nucleotides present in specialized intracellular granules and that are specifically extruded from the platelet during the release reaction. Low platelet serotonin values were found in three of these patients, indicating that their platelets may lack the entire content of substances normally found in these granules. In all four of the patients with thrombocytopathia A, for which the name "storage pool disease" is proposed, platelet adenine uptake was normal, but increased hypoxanthine formation by resting cells was found in the three patients with low serotonin values. The breakdown of the ATP to inosine monophopshate and hypoxanthine during the release reaction was normal in all patients studied. Platelets from the patient with thrombasthenia were normal in all respects studied.

Inherited Platelet δ-Storage Pool Disease in Dogs Causing Severe Bleeding: An Animal Model for a Specific ADP Deficiency

1995 ◽  
Vol 74 (03) ◽  
pp. 949-953 ◽  
Author(s):  
Mary Beth Callan ◽  
Joel S Bennett ◽  
Deborah K Phillips ◽  
Mark E Haskins ◽  
James E Hayden ◽  
...  
Keyword(s):  
Adenine Nucleotide ◽  
Bleeding Disorder ◽  
Serotonin Uptake ◽  
Severe Bleeding ◽  
Minor Trauma ◽  
Dense Granules ◽  
Storage Pool ◽  
Normal Number ◽  
Platelet Disorder ◽  
Storage Pool Disease

SummaryThe nature of a disorder producing moderate to severe bleeding after minor trauma, venipuncture, and surgery was studied in 3 families of American cocker spaniel dogs. In the 5 affected dogs tested, platelet counts and measurements of plasma coagulant function and von Willcbrand factor were normal. However, bleeding times were prolonged in 4 of the 5 affected dogs tested, and platelet aggregation in response to ADP and collagen was consistently abnormal in 3, suggesting that the bleeding disorder was due to abnormal platelet function. Measurements of 14C-serotonin uptake and retention by the affected platelets were normal. However, their ADP content was decreased, while their ATP content was normal, resulting in a mean ATP/ADP ratio of 8.32, compared to a mean ratio of 1.9 in normal canine platelets. Electron microscopy revealed that the number and appearance of the dense granules in the affected platelets were indistinguishable from those of normal controls. These studies suggest that this bleeding disorder results from a deficient δ-granule storage pool of ADP; given the normal serotonin uptake and retention by affected platelets and the apparently normal number of dense granules, the ADP deficiency may be the consequence of a selective defect in δ-granule ADP transport. Additional studies of this unique platelet disorder will provide an opportunity to understand the mechanism of adenine nucleotide storage in platelet δ granules.

scholarly journals Platelet Alpha-Storage Pool Defect Combined with Non-Classic Delta-Storage Pool Deficiency - with a Severe Bleeding Tendency

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2557-2557
Author(s):  
Frauke Bergmann ◽  
Kathrin Schwierczek ◽  
Stefanie Sollfrank ◽  
Andreas Czwalinna ◽  
Joseph Erkel ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Adenine Nucleotides ◽  
Molecular Genetic ◽  
Surface Expression ◽  
Bleeding Disorder ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Normal Range ◽  
Storage Pool

Abstract Aims :We report about a 35 year old male patient with severe and frequent epistaxis and hematoma since infancy. He presented with mild thrombocytopenia and increased mean platelet volume. Von Willebrand's disease and subhemophilia had been excluded. Previously, he was diagnosed with immune thrombocytopenic purpura. He never underwent elective surgery. His parents were asymptomatic. However, his young daughter also suffers from severe bleeding symptoms and was referred to our coagulation outpatient clinic to investigate the bleeding disorder. Methods:Platelet function was assessed by light transmission-, lumi-aggregometry and flow cytometry. Lysates of gel-filtered platelets were analyzed for total granule P-selectin, CD63 and von Willebrand factor (VWF) content by Western blotting and for serotonin levels by ELISA, respectively. Molecular genetic analysis was performed using whole exome sequencing and pyrosequencing. Results: Platelet aggregation in response to ADP was not inducible. Platelet aggregation in response to epinephrine resulted in monophasic curves. Platelet aggregation in response to TRAP-6 or collagen was inducible but impaired and accompanied by disaggregation. In contrast, arachidonic acid- and U46619-induced platelet aggregation as well as ristocetin-induced platelet agglutination/aggregation was within the normal range. Also platelet surface expression of GPIIb/IIIa, GPIb/V/IX, GPVI and CD29 was normal. Activation of GPIIb/IIIa in response to ADP, convulxin or TRAP-6 was inducible but diminished and in response to epinephrine or arachidonic acid normal. P-selectin (alpha-granule marker) and CD63 (dense body/lysosome marker) surface expression was not inducible by thrombin or convulxin and markedly reduced in response to TRAP-6 and arachidonic acid. Immunoblot analysis of isolated platelets demonstrated pronouncedly decreased content of total P-selectin, VWF and CD63. Fluorescent staining of adenine nucleotides by mepacrine in patient's platelet dense bodies and secretion of ATP induced by arachidonic acid (normal aggregation) were absent. However, patient's platelet serotonin levels were within the normal range. The molecular genetic diagnostic showed an undescribed mutation in the GATA1 gene (c.886A>C hemizygot, p.T296P). The bioinformatic check confirmed a pathogenetic importance of this mutation located in the domain I of the C-terminal zinc finger. Conclusion: We describe the first case of a combined platelet alpha- and partial delta-storage pool disorder where the dense granules lack adenine nucleotides but contain normal levels of serotonin - causing a severe bleeding disorder. Disclosures No relevant conflicts of interest to declare.

The Utility of Thromboelastography As a Screening Test for Bleeding Disorders

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4352-4352 ◽  
Author(s):  
Ayesha N Zia ◽  
Muhammad Fawad Bilal ◽  
Madhvi Rajpurkar ◽  
Meera B. Chitlur ◽  
Michael Callaghan ◽  
...  
Keyword(s):  
Clinical Evaluation ◽  
Screening Test ◽  
Laboratory Testing ◽  
Bleeding Disorder ◽  
Factor Vii ◽  
Factor Xii ◽  
Bleeding Disorders ◽  
Factor Xi Deficiency ◽  
Storage Pool ◽  
Storage Pool Disease

Abstract Abstract 4352 Introduction: Accurate assessment of bleeding disorders requires a thorough clinical evaluation and appropriate laboratory testing process. These patients comprise a substantial proportion of consultations carried out by hematologists. The limitations of each screening test, and the heterogeneity of these disorders continue to make the diagnosis cumbersome for the practicing clinician. Plasma clotting times, such as the prothrombin time and activated partial thromboplastin time are the most frequently used screening tests to assess adequacy of hemostasis. Thromboelastography (TEG) lends the ability to assess hemostasis globally while also assessing the effects of platelets, leucocytes and red cells on coagulation. Aims: To determine the utility of TEG as an effective screening test for bleeding disorders Methods: Medical records of patients referred to Hematology Service from August 2006 through July 2011 were retrospectively reviewed after institutional review board approval. Results: One hundred ninety-five patients (125 females, 70 males: ages 0.1 to 20 years) were evaluated for a bleeding disorder based on either bleeding symptoms or abnormal routine clotting tests and had TEG performed with low dose tissue factor (1:190 000 concentration). Most common symptoms were epistaxis (83/195), bruising (67/195), menorrhagia (48/195), surgical bleeding (16/195). Twenty-nine patients were diagnosed with a bleeding disorder based on clinical evaluation and laboratory testing. Type 1 vonWillebrand disease (vWD) was diagnosed in 16 patients, heterozygous factor VII deficiency in 6 patients, factor XII deficiency in 3 patients, factor XI deficiency in 2 patients and platelet delta storage pool disease in 1 patient. One patient was a symptomatic hemophilia carrier. Preliminary analysis revealed that among the vWD patients, only 1 patient demonstrated abnormalities in all parameters of TEG [Prolonged Reaction time (R Time), k time (rate of clot formation) and decreased Maximum amplitude (MA)] and 2 showed prolonged R and k time without concomitant decrease in MA. In patients with heterozygous factor VII deficiency, only 2 of 4 patients showed prolonged R and k times. The symptomatic hemophilia carrier, 1 of 3 with factor XII and 1 of 2 patients with factor XI deficiency had prolonged R as their sole abnormality. TEG was completely normal in the patient with platelet delta storage pool disease. The sensitivity of the R time to diagnose a clotting factor (including low factor VIII with vWD) deficiency was only 58% with a specificity of 78%. R time correlated with PTT and PT in up to 50% (vWD: 12%, FVII deficiency: 33%, FXII: 33%, FXI: 50%) of the patients. R time was also prolonged in 46/166 (28%) patients without a definitive bleeding disorder, however 10 of these patients had a lupus anticoagulant. Conclusion: In our study of 195 patients referred for evaluation of bleeding symptoms or abnormal coagulation tests, TEG was of limited value in identifying congenital coagulation defects with both poor sensitivity and specificity. Future studies could examine different agonists or conditions for TEG that may improve its sensitivity for detection of congenital bleeding disorders. Disclosures: No relevant conflicts of interest to declare.

Detection of an Acquired Platelet Storage Pool Disease in Three Patients with a Myeloproliferative Disorder

1979 ◽  
Vol 42 (02) ◽  
pp. 794-796 ◽  
Author(s):  
Francine Rendu ◽  
Marilyne Lebret ◽  
Alan Nurden ◽  
Jacques P Caen
Keyword(s):  
Myeloproliferative Disorder ◽  
Storage Pool ◽  
Platelet Storage ◽  
Storage Pool Disease

A Case Study of a Large and Rare Pleomorphic Liposarcoma in The Chest Area

2020 ◽  
Author(s):  
Yuanjun Cheng
Keyword(s):  
Delayed Diagnosis ◽  
Clinical Work ◽  
Radical Excision ◽  
Pathological Findings ◽  
Chest Tightness ◽  
Pleomorphic Liposarcoma ◽  
Left Chest ◽  
Specific Symptoms ◽  
Work Up

Pleomorphic liposarcoma rarely develops in the chest area. This report presents a primary pleomorphic liposarcoma that was discovered in the left chest area of a 74-year-old female patient. The patient had presented specific symptoms, including cough, chest tightness and shortness of breath. A radical excision of the tumor was performed. The tumor was extremely large (27 cm - 24 cm- 10 cm) and completely encapsulated. Upon histological examination, it was diagnosed as a giant, pleomorphic liposarcoma. Thereafter, non-specific radiological and endoscopic results during clinical work-up delayed diagnosis until post-operative histology were gathered. In this report, the case-specific clinical and radiological diagnostic challenges are discussed, as well as the relevant surgical and pathological findings.

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