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Bernard Soulier Sendromlu Hastalarda Klinik ve Genotipik Bulgular: Tek Merkez Deneyimi

Yıl 2017, Cilt: 11 Sayı: 1, 51 - 55, 01.04.2017

Öz

Amaç: Bernard Soulier Sendromu (BSS), bir herediter kanama bozukluğu olup, makrotrombositopeni ve uzamış kanama zamanı ile karakterizedir. BSS, trombosit yüzeyinde hasarlı damar duvarına yapışmadan sorumlu GpIb/V/IX kompleksinin yokluğu veya disfonksiyonundan kaynaklanır. Çalışmada, merkezimizde takip edilen BSS tanılı olguların klinik, laboratuvar bulguları ve mutasyon analizi değerlendirilmiştir.Gereç ve Yöntemler: Çalışmaya Meram Tıp Fakültesi Çocuk Hematoloji Bilim Dalında takip edilen 7 BSS olgusu dâhil edildi. Olguların klinik ve laboratuvar bulguları hastaların tıbbi dosya kayıtlarından derlendi. Mutasyon analizi için sırasıyla DNA izolasyonu, polimeraz zincir reaksiyonu ve DNA pürifikasyonu ve DNA dizi analizi yöntemleri kullanıldı. Elde edilen DNA numuneleri, GP1BA (NM_000173.4), GP1BB (NM_000407.4), ve GP9 (NM_000174.3) mutasyonları açısından incelendi. Oranların karşılaştırılmasında Fischer’in exact testi kullanıldı.Bulgular: Olguların yaşları 8.5 yaş ile 29 yaş arasında değişmekteydi (ortanca 24 yaş). Olguların hepsinin cinsiyeti kızdı. Tanı alma yaşları 7 ay ile 8 yaş arasında değişiyordu (ortanca 30 ay). Hastalarda görülen kanama tipleri; epistaksis (%71), diş eti kanaması (%71), gastrointestinal kanama (%43), menoraji (%71), gastorintestinal kanama (%28), viseral kanama %14, cerrahi sonrası kanama (%5)’di. Olguların hepsinde makrotrombositopeni vardı. Trombosit fonksiyon testlerinde ADP, epinefrin ve kollajene cevapnormal, ristosetine cevap bozuktu. Akım sitometrik olarak trombosit yüzeyinde GpIb/V/IX ekspresyonu 6 olguda düşük, bir olguda ise normaldi. Genetik olarak 6 olguda GP1BB geninde [homozigot c.233T>G. p.Leu78Arg ve c.[470T>A(+)472_473del(CT)] (p.Leu157GlnfsX151)], bir olguda GP1BA geninde (homozigot c.1A>C) mutasyon saptandı. Mutasyon tipi ile klinik bulgular arasında korelasyon saptanmadı (p>0.05).Sonuç: Çalışmada BSS tanılı olguların klinik ve laboratuvar bulguları ile mutasyon analizi değerlendirilmiştir. BSS hastaları için mukokutanöz kanamalar önemli bir problem oluşturmaktadır. Özellikle adet gören kız çocuklarında transfüzyon gereksinimi ortaya çıkabilmektedir. Çalışmada, BSS’li hastalarda yeni tanımlanan mutasyonlar gösterildiği için literatüre katkı sağlayacaktır. BSS’li hastalarda klinik bulgular ile mutasyon arasındaki ilişkinin tanımlanabilmesi için daha kapsamlı çalışmalara ihtiyaç vardır.

Kaynakça

  • Lambert MP, Poncz M. Inherited Platelet Disorders. In: Orkin SH, Fisher DE, Ginsburg D, Look AT, Lux SE, Nathan DG (eds). Nathan and Oski’s Hematology and Oncology of Infancy and Childhood. 8th ed. Philadelphia: Elsevier Saunders, 2015:1167-203.
  • Diz-Küçükkaya R. Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome. Hematology Am Soc Hematol Educ Program 2013;2013:268-75.
  • Lanza F. Bernard-Soulier syndrome (hemorrhagiparous throm- bocytic dystrophy). Orphanet J Rare Dis 2006;1:46.
  • Balduini CL, Pecci A, Noris P. Diagnosis and management of inhe- rited thrombocytopenias. Semin Thromb Hemost 2013;39:161-71.
  • Savoia A, Pastore A, De Rocco D, Civaschi E, Di Stazio M, Bottega R, et al. Clinical and genetic aspects of Bernard-Soulier syndrome: Searching for genotype/phenotype correlations. Haematologica 2011;96:417-23.
  • Jenkins CS, Phillips DR, Clemetson KJ, Meyer D, Larrieu MJ, Luscher EF. Platelet membrane glycoproteins implicated in ristocetin-induced aggregation. Studies of the proteins on platelets from patients with Bernard-Soulier syndrome and von Willebrand’s disease. J Clin Invest 1976;57:112-24.
  • Cohn RJ, Sherman GG, Glencross DK. Flow cytometric analysis of platelet surface glycoproteins in the diagnosis of Bernard-Soulier syndrome. Pediatr Hematol Oncol 1997;14:43-50.
  • Balduini CL, Savoia A. Genetics of familial forms of thrombocyto- penia. Hum Genet 2012;131:1821-32.
  • Savoia A, Kunishima S, De Rocco D, Zieger B, Rand ML, Pujol- Moix N, et al. Spectrum of the mutations in Bernard-Soulier syndrome. Hum Mutat 2014;35:1033-45.
  • Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard- Soulier syndrome. Blood 1998;91:4397-418.
  • Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: Results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006;4:766-73.
  • Page LK, Psaila B, Provan D, Michael Hamilton J, Jenkins JM, Elish AS, et al. The immune thrombocytopenic purpura (ITP) bleeding score: Assessment of bleeding in patients with ITP. Br J Haematol 2007;138:245-8.
  • O’Brien SH. Bleeding scores: Are they really useful? Hematology Am Soc Hematol Educ Program 2012;2012:152-6.
  • McKay H, Derome F, Haq MA, Whittaker S, Arnold E, Adam F, et al. Bleeding risks associated with inheritance of the Quebec platelet disorder. Blood 2004;104:159-65.
  • Borhany M, Fatima H, Naz A, Patel H, Shamsi T. Pattern of bleeding and response to therapy in Glanzmann thrombasthenia. Haemophilia 2012;18:e423-5.
  • Diz-Küçükkaya R, Lopez JA. Inherited disorders of platelets: Membrane glycoprotein disorders. Hematol Oncol Clin North Am 2013;27:613-27.
  • Ramasamy I. Inherited bleeding disorders: Disorders of platelet adhesion and aggregation. Crit Rev Oncol Hematol 2004;49:1-35.

Syndrome: A Single Center Experience Clinical and Genotypic Findings in Patients with Bernard Soulier

Yıl 2017, Cilt: 11 Sayı: 1, 51 - 55, 01.04.2017

Öz

Objective: The Bernard Soulier Syndrome (BSS) is an inherited bleeding disorder characterized by macrothrombocytopenia and prolonged bleeding time. BSS results from the dysfunction or absence of GpIb/V/IX complex, which mediates platelet adhesion to a damaged vascular wall, on the platelet surface. In this study, we evaluated the clinical and laboratory findings and mutation analysis in patients with BSS followed at our center.Material and Methods: The study included seven BSS followed at the Meram Faculty of Medicine, Department of Pediatric Hematology. Clinical and laboratory findings were obtained from the medical records of the patients. DNA isolation, polymerase chain reaction, DNA purification and DNA sequence analysis were used to determine mutation analysis. Obtained DNA samples investigated for GP1BA (NM_000173.4), GP1BB (NM_000407.4), and GP9 (NM_000174.3) mutations. Fischer’s exact test was used for the comparison of ratios.results: The ages of patients were varied from 8.5 years to 29 years (median 24 years). All of the patients were females. Age at diagnosis was varied from 7 months to 8 years (median 30 months). Bleeding phenotypes of the patients were as follows: epistaxis (71%), gum bleeding (71%), cutaneous bleeding (43%), menorrhagia (71%), gastrointestinal bleeding (28%), visceral bleeding (14%), and bleeding after surgery (5%). All of the patients had macrothrombocytopenia, and decreased aggregation response to ristocetin and normal response to ADP, epinephrine and collagen in platelet function tests. In flow
cytometric analysis, expression of the GpIb/V/IX complex on platelet surface was low in 6 patients and normal in one patient. Six patients
had GP1BB mutations [homozygous c.233T>G, p.Leu78Arg and c.[470T>A(+)472_473del(CT)] (p.Leu157GlnfsX151)] whereas one
patient had the GP1BB mutation (homozygous c.1A>C). There was no correlation between clinical findings and mutation types (p>0.05).
Conclusion: Clinical and laboratory findings and mutation analysis of patients with BSS were evaluated in this study. Mucocutaneous
bleeding is an important problem for patients with BSS. Girls may need a blood transfusion during menstruation. The mutations described
in this study are novel mutations. This study will contribute to the literature because of the newly identified mutations in BSS patients.
Comprehensive studies are needed to determine the relationship between clinical and genotypic findings of BSS patients.

Kaynakça

  • Lambert MP, Poncz M. Inherited Platelet Disorders. In: Orkin SH, Fisher DE, Ginsburg D, Look AT, Lux SE, Nathan DG (eds). Nathan and Oski’s Hematology and Oncology of Infancy and Childhood. 8th ed. Philadelphia: Elsevier Saunders, 2015:1167-203.
  • Diz-Küçükkaya R. Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome. Hematology Am Soc Hematol Educ Program 2013;2013:268-75.
  • Lanza F. Bernard-Soulier syndrome (hemorrhagiparous throm- bocytic dystrophy). Orphanet J Rare Dis 2006;1:46.
  • Balduini CL, Pecci A, Noris P. Diagnosis and management of inhe- rited thrombocytopenias. Semin Thromb Hemost 2013;39:161-71.
  • Savoia A, Pastore A, De Rocco D, Civaschi E, Di Stazio M, Bottega R, et al. Clinical and genetic aspects of Bernard-Soulier syndrome: Searching for genotype/phenotype correlations. Haematologica 2011;96:417-23.
  • Jenkins CS, Phillips DR, Clemetson KJ, Meyer D, Larrieu MJ, Luscher EF. Platelet membrane glycoproteins implicated in ristocetin-induced aggregation. Studies of the proteins on platelets from patients with Bernard-Soulier syndrome and von Willebrand’s disease. J Clin Invest 1976;57:112-24.
  • Cohn RJ, Sherman GG, Glencross DK. Flow cytometric analysis of platelet surface glycoproteins in the diagnosis of Bernard-Soulier syndrome. Pediatr Hematol Oncol 1997;14:43-50.
  • Balduini CL, Savoia A. Genetics of familial forms of thrombocyto- penia. Hum Genet 2012;131:1821-32.
  • Savoia A, Kunishima S, De Rocco D, Zieger B, Rand ML, Pujol- Moix N, et al. Spectrum of the mutations in Bernard-Soulier syndrome. Hum Mutat 2014;35:1033-45.
  • Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard- Soulier syndrome. Blood 1998;91:4397-418.
  • Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: Results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006;4:766-73.
  • Page LK, Psaila B, Provan D, Michael Hamilton J, Jenkins JM, Elish AS, et al. The immune thrombocytopenic purpura (ITP) bleeding score: Assessment of bleeding in patients with ITP. Br J Haematol 2007;138:245-8.
  • O’Brien SH. Bleeding scores: Are they really useful? Hematology Am Soc Hematol Educ Program 2012;2012:152-6.
  • McKay H, Derome F, Haq MA, Whittaker S, Arnold E, Adam F, et al. Bleeding risks associated with inheritance of the Quebec platelet disorder. Blood 2004;104:159-65.
  • Borhany M, Fatima H, Naz A, Patel H, Shamsi T. Pattern of bleeding and response to therapy in Glanzmann thrombasthenia. Haemophilia 2012;18:e423-5.
  • Diz-Küçükkaya R, Lopez JA. Inherited disorders of platelets: Membrane glycoprotein disorders. Hematol Oncol Clin North Am 2013;27:613-27.
  • Ramasamy I. Inherited bleeding disorders: Disorders of platelet adhesion and aggregation. Crit Rev Oncol Hematol 2004;49:1-35.
Toplam 17 adet kaynakça vardır.

Ayrıntılar

Diğer ID JA45AP95ZC
Bölüm Research Article
Yazarlar

Hüseyin Tokgöz Bu kişi benim

Ümran Çalışkan Bu kişi benim

Yayımlanma Tarihi 1 Nisan 2017
Gönderilme Tarihi 1 Nisan 2017
Yayımlandığı Sayı Yıl 2017 Cilt: 11 Sayı: 1

Kaynak Göster

Vancouver Tokgöz H, Çalışkan Ü. Syndrome: A Single Center Experience Clinical and Genotypic Findings in Patients with Bernard Soulier. Türkiye Çocuk Hast Derg. 2017;11(1):51-5.

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