Recent Advances in the Diagnosis and Molecular Pathogenesis of Congenital Thrombocytopenia with Small or Normal-Sized Platelets

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1 The Japanese Journal of Pediatric Hematology/Oncology vol. 50(2): , ,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 * ysasahara@med.tohoku.ac.jp ITP

2 187 1 ITP ITP ITP mean platelet volume: MPV MPV μm 8 μm 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

3 WAS XLT 1 XLT 2 XLT 3 WAS 4 WAS 5 WAS and/or and/or XLT ITP 3 WAS XLT MPV: 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 2 Wiskott-Aldrich Autosomal recessive WAS 7 9 WAS WASP WASP WASP WIP WAS WIP 1 WASP WIP

4 189 2 WASP 1 WIP WASP WIP WASP WASP WASP 7,8 4 WIP 2012 WIP ITP ITP 1 Congenital amegakaryocytic thrombocytopenia: CAMT 10,11 3 thrombopoietin TPO MPL TPO MPL 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

5 Thrombocytopenia with absent radii: TAR 13 X RNA 4 1 Y14 RBM8A RNA binding motif protein 8A null 2 single nucleotide polymorphism SNP RBM8A 1q RBM8A null SNP RBM8A Y14 4 Familial platelet disorder with propensity to myeloid malignancy 14 35% MDS AML ITP 7 45 MDS/AML RUNX1 AML Autosomal domi nant thrombocytopenia, thrombocytopenia 2: THC2 15,16 GP Ia α TPO ANKRD26 Ankyrin repeat domain-containing protein 26 5' c Cytochrome c mutation 17 7p15.2 CYCS G41S 1 IV ITP ITP TEL: FAX: ysasahara@med.tohoku.ac.jp TEL: FAX: 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, : , 2012.

6 191 3 Wiskott-Aldrich 28: , Wiskott-Aldrich WIP 21: , Imai K, Morio T, Zu Y, et al: Clinical course of patients with WASP gene mutations. Blood, 103: , Albert MH, Bittner TC, Nonoyama S, et al: X-linked thrombocytopenia(xlt) due to WAS mutations: clinical characteristics, long-term outcome and treatment options. Blood, 115: , Sasahara Y, Rachid R, Byrne MJ, et al: Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Mol Cell, 10: , de la Fuente MA, Sasahara Y, Calamito M, et al: WIP is a chaperone for Wiskott-Aldrich syndrome protein (WASP). Proc Natl Acad Sci USA, 104: , Lanzi G, Moratto D, Vairo D, et al: A novel primary immunodeficiency due to deficiency in the WASP-interacting protein WIP. J Exp Med, 209: 29 34, Ballmaier M, Germeshausen M: Advances in the understanding of congenital amegakaryocytic thrombocytopenia. Br J Haematol, 146: 3 16, Ballmaier M, Germeshausen M: Congenital amegakaryocytic thrombocytopenia: clinical presentation, diagnosis, and treatment. Semin Thromb Hemost, 37: , Thompson AA, Nguyen LT: Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet, 26: , Albers CA, Paul DS, Schulze H, et al: Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet, 44: , Owen CJ, Toze CL, Koochin A, et al: Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood, 112: , Pippucci T, Savoia A, Perrotta S, et al: Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet, 88: , Noris P, Perrotta S, Seri M, et al: Mutations in ANKRD26 are responsible for frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood, 117: , Morison IM, Cramer Bordé EM, Cheesman EJ, et al: A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nat Genet, 40: , 2008.

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