The Japanese Journal of Pediatric Hematology/Oncology vol. 50(2): 186 191, 2013 1,2 * 1 2 1 2 Recent Advances in the Diagnosis and Molecular Pathogenesis of Congenital Thrombocytopenia with Small or Normal-Sized Platelets Yoji Sasahara 1,2 *, Meri Ouchi 1, Masue Imaizumi 2 1 Department of Pediatrics, Tohoku University Graduate School of Medicine 2 Committee of Platelet Disorders, The Japanese Society of Pediatric Hematology/Oncology Abstract Childhood thrombocytopenia includes idiopathic thrombocytopenic purpura (ITP) as well as congenital thrombocytopenia caused by genetic mutations. We have to exclude congenital thrombocytopenia in patients with chronic and refractory ITP. To realize definite diagnosis of congenital thrombocytopenia with small or normal-sized platelets, accurate and clinically applicable methods for genetic diagnosis are required. Recent advances revealed new disease entities and genetic backgrounds of the diseases. In this paper, we focused on the clinical manifestation, pathogenesis and diagnosis of congenital thrombocytopenia with small or normal-sized platelets. Thrombocytopenia with small platelets includes Wiskott-Aldrich syndrome and X-linked thrombocytopenia caused by mutations in WASP and the newly identified molecule, WIP. Congenital thrombocytopenia with normal-sized platelets includes six well-characterized diseases: i.e. congenital amegakaryocytic thrombocytopenia, congenital thrombocytopenia with radio-ulnar synostosis, thrombocytopenia with absent radii, familial platelet disorder with predisposition to acute myelogeneous leukemia, autosomal dominant thrombocytopenia, and cytochrome C mutation. This article is clinically applicable for making differential diagnosis of congenital thrombocytopenia with small or normal-sized platelets, and the choice of appropriate therapy in patients with chronic and refractory ITP. Key words: congenital thrombocytopenia, idiopathic thrombocytopenic purpura, small platelets, normal-sized platelets, genetic diagnosis idiopathic thrombocytopenic purpura ITP ITP ITP ITP Wiskott-Aldrich X X WASP WIP c 6 ITP I 2012 10 18 2013 2 21 * 980-8575 1-1 E-mail: ysasahara@med.tohoku.ac.jp ITP
187 1 ITP ITP ITP mean platelet volume: MPV MPV 2 2 4 μm 8 μm 1 1 1 2 3 4 ITP ITP 1 II 2 2 III 1 1 X Wiskott-Aldrich X-linked WAS X X-linked thrombocytopenia: XLT 3 7 X X-linked WAS 3 WASP WASP 2 Wiskott-Aldrich Wiskott-Aldrich syndrome: WAS) X AR WASP WIP X X-linked thrombocytopenia: XLT) X WASP Congenital amegakaryocytic thrombocytopenia) Congenital thrombocytopenia with radio-ulnar synostosis) Thrombocytopenia with absent radii) Familial platelet disorder with propensity to myeloid malignancy) Autosomal dominant thrombocytopenia, thrombocytopenia 2: THC2) AR MPL AD HOXA11 AR RBM8A AD RUNX1 MDS AD ANKRD26 GPIa α c Cytochrome c mutation) AD CYCS X X AD AR
188 50 2 2013 3 WAS XLT 1 XLT 2 XLT 3 WAS 4 WAS 5 WAS and/or and/or XLT ITP 3 WAS XLT MPV: 6.0 6.2 fl ITP WAS XLT ITP IgA B 60 1 WASP WASP T 3,4 WASP WASP-interacting protein, WIP WASP WAS 5 XLT event free survival 6 T B NK WASP 2 WASP WASP WASP PIDJ primary immunodeficiency database in Japan http://pidj.rcai.riken.jp/ 2 Wiskott-Aldrich Autosomal recessive WAS 7 9 WAS WASP WASP WASP WIP WAS WIP 1 WASP WIP
189 2 WASP 1 WIP WASP WIP WASP WASP WASP 7,8 4 WIP 2012 WIP 1 9 1 5.9 2 ITP ITP 1 Congenital amegakaryocytic thrombocytopenia: CAMT 10,11 3 thrombopoietin TPO MPL TPO MPL 100 2 Congenital thrombocytopenia with radio-ulnar synostosis 12 1 HOXA11 / HOXA11 4 WIP WIP WAS 1 WIP WASP 2 WASP WIP 3 WIP WIP --- --- WAS --- WASP --- WASP WIP WAS WIP
190 50 2 2013 10 3 Thrombocytopenia with absent radii: TAR 13 X RNA 4 1 Y14 RBM8A RNA binding motif protein 8A null 2 single nucleotide polymorphism SNP 1 53 51 RBM8A 1q21.1 2 RBM8A null SNP RBM8A Y14 4 Familial platelet disorder with propensity to myeloid malignancy 14 35% MDS AML ITP 7 45 MDS/AML RUNX1 AML1 20 5 Autosomal domi nant thrombocytopenia, thrombocytopenia 2: THC2 15,16 GP Ia α 10 3 8 4.7 TPO ANKRD26 Ankyrin repeat domain-containing protein 26 5'- 113 30 6 c Cytochrome c mutation 17 7p15.2 CYCS G41S 1 IV ITP ITP 1 980-8574 1-1 TEL: 022-717-7287 FAX: 022-717-7290 E-mail: ysasahara@med.tohoku.ac.jp 2 460-0001 4-1-1 TEL: 052-951-1111 FAX: 052-951-0664 E-mail: kunishis@nnh.hosp.go.jp 1 Alter BP: Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program, 29 39, 2007. 2 49: 382 386, 2012.
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