title: Analyses of Genetic and Clinical Parameters for Screening Patients With Inherited Thrombocytopenia with Small or Normal-Sized Platelets.
abstract: BACKGROUND
  Childhood thrombocytopenias include immune thrombocytopenic purpura (ITP) and inherited thrombocytopenia; the former is caused by autoantibodies to platelets, whereas the latter can be distinguished by platelet size and underlying genetic mutations. Due to limited methods for the definite diagnosis of ITP, genetic and clinical parameters are required for diagnosing inherited thrombocytopenias with small or normal-sized platelets.
  
  
  METHODS
  In total, 32 Japanese patients with thrombocytopenia with small or normal-sized platelets from 29 families were enrolled. All the patients were under 20 years of age, with family histories of early-onset thrombocytopenia and/or poor response to conventional therapies for ITP. Genotypes and clinical parameters were retrospectively evaluated according to the disease type.
  
  
  RESULTS
  Twelve cases of inherited thrombocytopenia were observed. We identified chromosomal deletions within the WASP gene in two patients with Wiskott-Aldrich syndrome; a missense mutation in a patient with X-linked thrombocytopenia; and mutations in the RUNX1 gene of five patients with familial platelet disorder with propensity to acute myelogenous leukemia, and in the ANKRD26 gene of four patients with autosomal dominant thrombocytopenia-2. All 12 carried germline mutations, three of which were de novo. Furthermore, we observed significantly elevated serum thrombopoietin (TPO) levels and dysplasia of megakaryocytes in patients carrying the RUNX1 and ANKRD26 mutations.
  
  
  CONCLUSIONS
  Genetic analyses and detection of TPO levels and dysmegakaryopoiesis were clinically useful for screening patients with inherited thrombocytopenias, irrespective of the family history. We hypothesize that the WASP, RUNX1, and ANKRD26 genes are important for normal TPO signaling and the network underlying thrombopoiesis.
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan.|Department of Hematology and Oncology, Miyagi Children's Hospital, Miyagi, Japan.
authors.forename: Meri
authors.initials: M
authors.lastname: Ouchi-Uchiyama
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sasahara
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Department of Pediatrics, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Goi
authors.affiliation: Department of Pediatrics, University of Yamanashi, Yamanashi, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Nakane
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ikeno
authors.affiliation: Department of Pediatrics, Japanese Red Cross Narita Hospital, Chiba, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Noguchi
authors.affiliation: Department of Hematology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Naokuni
authors.initials: N
authors.lastname: Uike
authors.affiliation: Department of Pediatrics, Anjoh Kosei Hospital, Aichi, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyajima
authors.affiliation: Department of Pediatrics, Nishi-Kobe Medical Center, Hyogo, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Pediatrics, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Sugita
authors.affiliation: Department of Hematology and Oncology, Miyagi Children's Hospital, Miyagi, Japan.
authors.forename: Masue
authors.initials: M
authors.lastname: Imaizumi
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
mesh_terms: D000293:Adolescent; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D050676:Core Binding Factor Alpha 2 Subunit / Q000097:blood / Q000235:genetics; D005190:Family; D005260:Female; D030342:Genetic Diseases, Inborn / Q000097:blood / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009687:Nuclear Proteins / Q000097:blood / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics / Q000473:pathology; D034061:Thrombopoiesis / Q000235:genetics; D013926:Thrombopoietin / Q000097:blood / Q000235:genetics; D051316:Wiskott-Aldrich Syndrome Protein / Q000097:blood / Q000235:genetics
chemical_list: C583630:ANKRD26 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C493728:RUNX1 protein, human; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D013926:Thrombopoietin
keywords: ITP; molecular genetics; platelet disorders; thrombocytopenia