Human Genetics

, Volume 131, Issue 12, pp 1821–1832 | Cite as

Genetics of familial forms of thrombocytopenia

  • Carlo L. BalduiniEmail author
  • Anna Savoia
Review Paper


The joint application of clinical and genetic investigation to patients with inherited thrombocytopenias, as well as the availability of new methods for studying megakaryopoiesis, has greatly expanded the knowledge of these disorders in the last few years with regard to their etiology, pathogenesis and clinical aspects. In particular, new diseases have been described, as deriving from mutations in the genes FLNA, TUBB1, ITGA2/ITGB3, ANKRD26, CYCS, and ABCG5 or ABCG8. Moreover, forms previously considered separate entities were found to be different clinical aspects of a single disease. For instance, identification of MYH9 as the gene whose mutations cause the May–Hegglin anomaly led to the recognition that Sebastian platelet syndrome, Epstein syndrome, and Fechtner syndrome derive from mutations of the same gene and describe overlapping disorders. Despite these advances, knowledge of hereditary thrombocytopenias is still far from satisfactory because for approximately half of the patients it is not possible to formulate a definite diagnosis in that their illnesses has not yet been described. In this review, we provide a systematic description of hereditary thrombocytopenias as we know them today, giving special attention to genetic aspects.


Thrombocytopenia Periventricular Nodular Heterotopia Glanzmann Thrombasthenia Congenital Erythropoietic Porphyria Proplatelet Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by grants from the Telethon Fondazione Onlus (Grant GGP10089), the Italian Ministry of Education, University and Research (PRIN 2009), the IRCCS Burlo Garofolo, the IRCCS Policlinico San Matteo Foundation.


  1. Albers CA, Cvejic A, Favier R, Bouwmans EE, Alessi MC, Bertone P, Jordan G, Kettleborough RN, Kiddle G, Kostadima M, Read RJ, Sipos B, Sivapalaratnam S, Smethurst PA, Stephens J, Voss K, Nurden A, Rendon A, Nurden P, Ouwehand WH (2011) Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat Genet 43:735–737PubMedCrossRefGoogle Scholar
  2. Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, Krapels I, Nurden P, Ruivenkamp CA, Sambrook JG, Smith K, Stemple DL, Strauss G, Thys C, van Geet C, Newbury-Ecob R, Ouwehand WH, Ghevaert C (2012) Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet 44:435–439PubMedCrossRefGoogle Scholar
  3. Albert MH, Bittner TC, Nonoyama S, Notarangelo LD, Burns S, Imai K, Espanol T, Fasth A, Pellier I, Strauss G, Morio T, Gathmann B, Noordzij JG, Fillat C, Hoenig M, Nathrath M, Meindl A, Pagel P, Wintergerst U, Fischer A, Thrasher AJ, Belohradsky BH, Ochs HD (2010) X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. Blood 115:3231–3238PubMedCrossRefGoogle Scholar
  4. Balduini CL, Pecci A, Loffredo G, Izzo P, Noris P, Grosso M, Bergamaschi G, Rosti V, Magrini U, Ceresa IF, Conti V, Poggi V, Savoia A (2004) Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 91:129–140PubMedGoogle Scholar
  5. Balduini A, Pallotta I, Malara A, Lova P, Pecci A, Viarengo G, Balduini CL, Torti M (2008) Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes. J Thromb Haemost 6:1900–1907PubMedCrossRefGoogle Scholar
  6. Balduini A, Malara A, Pecci A, Badalucco S, Bozzi V, Pallotta I, Noris P, Torti M, Balduini CL (2009) Proplatelet formation in heterozygous Bernard–Soulier syndrome type Bolzano. J Thromb Haemost 7:478–484PubMedCrossRefGoogle Scholar
  7. Balduini CL, Pecci A, Savoia A (2011) Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. Br J Haematol 154:161–174PubMedCrossRefGoogle Scholar
  8. Ballmaier M, Germeshausen M (2011) Congenital amegakaryocytic thrombocytopenia: clinical presentation, diagnosis, and treatment. Semin Thromb Hemost 37:673–681PubMedCrossRefGoogle Scholar
  9. Béri-Dexheimer M, Latger-Cannard V, Philippe C, Bonnet C, Chambon P, Roth V, Grégoire MJ, Bordigoni P, Lecompte T, Leheup B, Jonveaux P (2008) Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions. Eur J Hum Genet 16:1014–1018PubMedCrossRefGoogle Scholar
  10. Bernard J, Soulier JP (1948) Sur une nouvelle variete de dystrphie thrombocytaire-hemorragipare congenitale. Sem Hop Paris 24:3217–3223PubMedGoogle Scholar
  11. Camitta BM, Rock A (1993) Acute lymphoidic leukemia in a patient with thrombocytopenia/absent radii (Tar) syndrome. Am J Pediatr Hematol Oncol 15:335–337PubMedGoogle Scholar
  12. Canales ML, Mauer AM (1967) Sex-linked hereditary thrombocytopenia as a variant of Wiskott–Aldrich syndrome. N Engl J Med 277:899–901PubMedCrossRefGoogle Scholar
  13. Castillo-Caro P, Dhanraj S, Haut P, Robertson K, Dror Y, Sharathkumar AA (2010) Proximal radio-ulnar synostosis with bone marrow failure syndrome in an infant without a HOXA11 mutation. J Pediatr Hematol Oncol 32:479–485PubMedCrossRefGoogle Scholar
  14. Chen Z, Naveiras O, Balduini A, Mammoto A, Conti MA, Adelstein RS, Ingber D, Daley GQ, Shivdasani RA (2007) The May anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway. Blood 110:171–179PubMedCrossRefGoogle Scholar
  15. Ciovacco WA, Raskind WH, Kacena MA (2008) Human phenotypes associated with GATA-1 mutations. Gene 427:1–6PubMedCrossRefGoogle Scholar
  16. Cohen MM Jr (2009) Perspectives on RUNX genes: an update. Am J Med Genet A 149A:2629–2646PubMedCrossRefGoogle Scholar
  17. Davis B, Toivio-Kinnucan M, Schuller S, Boudreaux MK (2008) Mutation in beta1-tubulin correlates with macrothrombocytopenia in Cavalier King Charles Spaniels. J Vet Intern Med 22:540–545PubMedCrossRefGoogle Scholar
  18. Drachman JG, Jarvik GP, Mehaffey MG (2000) Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10. Blood 96:118–125PubMedGoogle Scholar
  19. Ducrou W, Kimber RJ (1969) Stomatocytes, haemolytic anaemia and abdominal pain in Mediterranean migrants. Some examples of a new syndrome? Med J Aust 2:1087–1091Google Scholar
  20. Fabbro S, Kahr WH, Hinckley J, Wang K, Moseley J, Ryu GY, Nixon B, White JG, Bair T, Schutte B, Di Paola J (2011) Homozygosity mapping with SNP arrays confirms 3p21 as a recessive locus for gray platelet syndrome and narrows the interval significantly. Blood 117:3430–3434PubMedCrossRefGoogle Scholar
  21. Fadoo Z, Naqvi SM (2002) Acute myeloid leukemia in a patient with thrombocytopenia with absent radii syndrome. J Pediatr Hematol Oncol 24:134–135Google Scholar
  22. Favier R, Jondeau K, Boutard P, Grossfeld P, Reinert P, Jones C, Bertoni F, Cramer EM (2003) Paris-Trousseau syndrome: clinical, hematological, molecular data of ten new cases. Thromb Haemost 90:893–897PubMedGoogle Scholar
  23. Fox N, Priestley G, Papayannopoulou T, Kaushansky K (2002) Thrombopoietin expands hematopoietic stem cells after transplantation. J Clin Invest 110:389–394PubMedGoogle Scholar
  24. Gandhi MJ, Cummings CL, Drachman JG (2003) FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10. Hum Hered 55:66–70PubMedCrossRefGoogle Scholar
  25. Geddis AE (2009) Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Hematol Oncol Clin North Am 23:321–331PubMedCrossRefGoogle Scholar
  26. Ghevaert C, Salsmann A, Watkins NA, Schaffner-Reckinger E, Rankin A, Garner SF, Stephens J, Smith GA, Debili N, Vainchenker W, de Groot PG, Huntington JA, Laffan M, Kieffer N, Ouwehand WH (2008) A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia. Blood 111:3407–3414PubMedCrossRefGoogle Scholar
  27. Goodeve AC (2010) The genetic basis of von Willebrand disease. Blood Rev 24:123–134PubMedCrossRefGoogle Scholar
  28. Gresele P, Falcinelli E, Giannini S, D’Adamo P, D’Eustacchio A, Corazzi T, Mezzasoma AM, Di Bari F, Guglielmini G, Cecchetti L, Noris P, Balduini CL, Savoia A (2009) Dominant inheritance of a novel integrin beta3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families. Haematologica 94:663–669PubMedCrossRefGoogle Scholar
  29. Grossfeld PD, Mattina T, Lai Z, Favier R, Jones KL, Cotter F, Jones C (2004) The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Genet A 129A:51–61PubMedCrossRefGoogle Scholar
  30. Gunay-Aygun M, Zivony-Elboum Y, Gumruk F, Geiger D, Cetin M, Khayat M, Kleta R, Kfir N, Anikster Y, Chezar J, Arcos-Burgos M, Shalata A, Stanescu H, Manaster J, Arat M, Edwards H, Freiberg AS, Hart PS, Riney LC, Patzel K, Tanpaiboon P, Markello T, Huizing M, Maric I, Horne M, Kehrel BE, Jurk K, Hansen NF, Cherukuri PF, Jones M, Cruz P, Mullikin JC, Nurden A, White JG, Gahl WA, Falik-Zaccai T (2010) Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. Blood 116:4990–5001PubMedCrossRefGoogle Scholar
  31. Gunay-Aygun M, Falik-Zaccai TC, Vilboux T, Zivony-Elboum Y, Gumruk F, Cetin M, Khayat M, Boerkoel CF, Kfir N, Huang Y, Maynard D, Dorward H, Berger K, Kleta R, Anikster Y, Arat M, Freiberg AS, Kehrel BE, Jurk K, Cruz P, Mullikin JC, White JG, Huizing M, Gahl WA (2011) NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules. Nat Genet 43:732–734PubMedCrossRefGoogle Scholar
  32. Hamilton A, Ozelo M, Leggo J, Notley C, Brown H, Frontroth JP, Angelillo-Scherrer A, Baghaei F, Enayat SM, Favaloro E, Lillicrap D, Othman M (2011) Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. Thromb Haemost 105:501–508PubMedCrossRefGoogle Scholar
  33. Houeijeh A, Andrieux J, Saugier-Veber P, David A, Goldenberg A, Bonneau D, Fouassier M, Journel H, Martinovic J, Escande F, Devisme L, Bisiaux S, Chaffiotte C, Baux M, Kerckaert JP, Holder-Espinasse M, Manouvrier-Hanu S (2011) Thrombocytopenia-absent radius (TAR) syndrome: a clinical genetic series of 14 further cases. Impact of the associated 1q21.1 deletion on the genetic counselling. Eur J Med Genet 54:e471–e477PubMedCrossRefGoogle Scholar
  34. Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, Good RA, Hara T (1999) Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci USA 96:3132–3136Google Scholar
  35. Jacobsen P, Hauge M, Henningsen K, Hobolth N, Mikkelsen M, Philip J (1973) An (11;21) translocation in four generations with chromosome 11 abnormalities in the offspring. A clinical, cytogenetical, and gene marker study. Hum Hered 23:568–585PubMedCrossRefGoogle Scholar
  36. Jayo A, Conde I, Lastres P, Martínez C, Rivera J, Vicente V, González-Manchón C (2010) L718P mutation in the membrane-proximal cytoplasmic tail of beta 3 promotes abnormal alpha IIb beta 3 clustering and lipid microdomain coalescence, and associates with a thrombasthenia-like phenotype. Haematologica 95:1158–1166PubMedCrossRefGoogle Scholar
  37. Kahr WH, Hinckley J, Li L, Schwertz H, Christensen H, Rowley JW, Pluthero FG, Urban D, Fabbro S, Nixon B, Gadzinski R, Storck M, Wang K, Ryu GY, Jobe SM, Schutte BC, Moseley J, Loughran NB, Parkinson J, Weyrich AS, Di Paola J (2011) Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome. Nat Genet 43:738–740PubMedCrossRefGoogle Scholar
  38. Kidambi S, Patel SB (2008) Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J Clin Pathol 61:588–594PubMedCrossRefGoogle Scholar
  39. Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, König R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S (2007) Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet 80:232–240PubMedCrossRefGoogle Scholar
  40. Kunishima S, Imai T, Hamaguchi M, Saito H (2006) Novel heterozygous missense mutation in the second leucine rich repeat of GPIbalpha affects GPIb/IX/V expression and results in macrothrombocytopenia in a patient initially misdiagnosed with idiopathic thrombocytopenic purpura. Eur J Haematol 76:348–355PubMedCrossRefGoogle Scholar
  41. Kunishima S, Kobayashi R, Itoh TJ, Hamaguchi M, Saito H (2009) Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly. Blood 113:458–461PubMedCrossRefGoogle Scholar
  42. Kunishima S, Kashiwagi H, Otsu M, Takayama N, Eto K, Onodera M, Miyajima Y, Takamatsu Y, Suzumiya J, Matsubara K, Tomiyama Y, Saito H (2011) Heterozygous ITGA2B R995 W mutation inducing constitutive activation of the {alpha}IIb{beta}3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia. Blood 117(20):5479–5484PubMedCrossRefGoogle Scholar
  43. Larson MK, Watson SP (2006) Regulation of proplatelet formation and platelet release by integrin alpha IIb beta3. Blood 108:1509–1514PubMedCrossRefGoogle Scholar
  44. Liang HP, Morel-Kopp MC, Curtin J, Wilson M, Hewson J, Chen W, Ward CM (2007) Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients. Thromb Haemost 98:1298–1308PubMedGoogle Scholar
  45. Liew E, Owen CJ (2011) Familial myelodysplastic syndromes: a review of the literature. Haematologica 96:1536–1542PubMedCrossRefGoogle Scholar
  46. Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC (1998) Bernard–Soulier syndrome. Blood 91:4397–4418PubMedGoogle Scholar
  47. Luo SZ, Mo X, Afshar-Kharghan V, Srinivasan S, Lopez JA, Li R (2007) Glycoprotein Iba forms disulfide bonds with 2 glycoprotein Ib subunits in the resting platelet. Blood 109:603–609PubMedCrossRefGoogle Scholar
  48. Matheny CJ, Speck ME, Cushing PR, Zhou Y, Corpora T, Regan M, Newman M, Roudaia L, Speck CL, Gu TL, Griffey SM, Bushweller JH, Speck NA (2007) Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles. EMBO J 26:1163–1175PubMedCrossRefGoogle Scholar
  49. Mattina T, Perrotta CS, Grossfeld P (2009) Jacobsen syndrome. Orphanet J Rare Dis 4:9PubMedCrossRefGoogle Scholar
  50. Miller JL, Lyle VA, Cunningham D (1992) Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ib alpha leucine tandem repeat occurring in patients with an autosomal dominant variant of Bernard–Soulier disease. Blood 79:439–446PubMedGoogle Scholar
  51. Morison IM, Cramer Bordé EM, Cheesman EJ, Cheong PL, Holyoake AJ, Fichelson S, Weeks RJ, Lo A, Davies SM, Wilbanks SM, Fagerlund RD, Ludgate MW, da Silva Tatley FM, Coker MS, Bockett NA, Hughes G, Pippig DA, Smith MP, Capron C, Ledgerwood EC (2008) A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nat Genet 40:387–389PubMedCrossRefGoogle Scholar
  52. Noris P, Pecci A, Di Bari F, Di Stazio MT, Di Pumpo M, Ceresa I, Arezzi N, Ambaglio C, Savoia A, Balduini CL (2004) Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients. Haematologica 89:1219–1225PubMedGoogle Scholar
  53. Noris P, Perrotta S, Seri M, Pecci A, Gnan C, Loffredo G, Pujol-Moix N, Zecca M, Scognamiglio F, De Rocco D, Punzo F, Melazzini F, Scianguetta S, Casale M, Marconi C, Pippucci T, Amendola G, Notarangelo LD, Klersy C, Civaschi E, Balduini CL, Savoia A (2011) Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood 117:6673–6680PubMedCrossRefGoogle Scholar
  54. Noris P, Perrotta S, Bottega R, Pecci A, Melazzini F, Civaschi E, Russo S, Magrin S, Loffredo G, Di Salvo V, Russo G, Casale M, De Rocco D, Grignani C, Cattaneo M, Baronci C, Dragani A, Albano V, Jankovic M, Scianguetta S, Savoia A, Balduini CL (2012) Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIb{alpha} (Bolzano mutation). Haematologica 97:82–88PubMedCrossRefGoogle Scholar
  55. Nurden AT, Nurden P (2007) The gray platelet syndrome: clinical spectrum of the disease. Blood Rev 21:21–36PubMedCrossRefGoogle Scholar
  56. Nurden P, Debili N, Coupry I, Bryckaert M, Youlyouz-Marfak I, Solé G, Pons AC, Berrou E, Adam F, Kauskot A, Lamazière JM, Rameau P, Fergelot P, Rooryck C, Cailley D, Arveiler B, Lacombe D, Vainchenker W, Nurden A, Goizet C (2011a) Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome. Blood 118:5928–5937PubMedCrossRefGoogle Scholar
  57. Nurden AT, Fiore M, Nurden P, Pillois X (2011b) Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. Blood 118:5996–6005PubMedCrossRefGoogle Scholar
  58. Othman M (2011) Platelet-type Von Willebrand disease: three decades in the life of a rare bleeding disorder. Blood Rev 25:147–153PubMedCrossRefGoogle Scholar
  59. Othman M, Notley C, Lavender FL, White H, Byrne CD, Lillicrap D, O’Shaughnessy DF (2005) Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease. Blood 105:4330–4336PubMedCrossRefGoogle Scholar
  60. Pai SY, Notarangelo LD (2010) Hematopoietic cell transplantation for Wiskott–Aldrich syndrome: advances in biology and future directions for treatment. Immunol Allergy Clin North Am 30:179–194PubMedCrossRefGoogle Scholar
  61. Parrini E, Ramazzotti A, Dobyns WB, Mei D, Moro F, Veggiotti P, Marini C, Brilstra EH, Dalla Bernardina B, Goodwin L, Bodell A, Jones MC, Nangeroni M, Palmeri S, Said E, Sander JW, Striano P, Takahashi Y, Van Maldergem L, Leonardi G, Wright M, Walsh CA, Guerrini R (2006) Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations. Brain 129:1892–1906PubMedCrossRefGoogle Scholar
  62. Pecci A, Panza E, Pujol-Moix N, Klersy C, Di Bari F, Bozzi V, Gresele P, Lethagen S, Fabris F, Dufour C, Granata A, Doubek M, Pecoraro C, Koivisto PA, Heller PG, Iolascon A, Alvisi P, Schwabe D, De Candia E, Rocca B, Russo U, Ramenghi U, Noris P, Seri M, Balduini CL, Savoia A (2008) Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat 29:409–417PubMedCrossRefGoogle Scholar
  63. Pecci A, Malara A, Badalucco S, Bozzi V, Torti M, Balduini CL, Balduini A (2009) Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation. Thromb Haemost 102:90–96PubMedGoogle Scholar
  64. Pecci A, Bozzi V, Panza E, Barozzi S, Gruppi C, Seri M, Balduini CL (2011) Mutations responsible for MYH9-related thrombocytopenia impair SDF-1-driven migration of megakaryoblastic cells. Thromb Haemost 106:693–704Google Scholar
  65. Pecci A, Biino G, Fierro T, Bozzi V, Mezzasoma A, Noris P, Ramenghi U, Loffredo G, Fabris F, Momi S, Magrini U, Pirastu M, Savoia A, Balduini C, Gresele P (2012) Alteration of liver enzymes is a feature of the Myh9-related disease syndrome. PLoS One 7(4):e35986PubMedCrossRefGoogle Scholar
  66. Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP (2007) Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 109:2618–2621PubMedCrossRefGoogle Scholar
  67. Pippucci T, Savoia A, Perrotta S, Pujol-Moix N, Noris P, Castegnaro G, Pecci A, Gnan C, Punzo F, Marconi C, Gherardi S, Loffredo G, De Rocco D, Scianguetta S, Barozzi S, Magini P, Bozzi V, Dezzani L, Di Stazio M, Ferraro M, Perini G, Seri M, Balduini CL (2011) 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 88:115–120PubMedCrossRefGoogle Scholar
  68. Raccuglia G (1971) Gray platelet syndrome. A variety of qualitative platelet disorder. Am J Med 51:818–828PubMedCrossRefGoogle Scholar
  69. Raslova H, Komura E, Le Couédic JP, Larbret F, Debili N, Feunteun J, Danos O, Albagli O, Vainchenker W, Favier R (2004) FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia. J Clin Invest 114:77–84PubMedGoogle Scholar
  70. Rees DC, Iolascon A, Carella M, O’marcaigh AS, Kendra JR, Jowitt SN, Wales JK, Vora A, Makris M, Manning N, Nicolaou A, Fisher J, Mann A, Machin SJ, Clayton PT, Gasparini P, Stewart GW (2005) Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol 130:297–309PubMedCrossRefGoogle Scholar
  71. Savoia A, Del Vecchio M, Totaro A et al (1999) An autosomal dominant thrombocytopenia gene maps to chromosomal region 10p. Am J Hum Genet 65:1401–1405PubMedCrossRefGoogle Scholar
  72. Savoia A, Balduini C, Savino M, Noris N, Del Vecchio M, Perotta S, Belletti S, Poggi V, Iolascon A (2001) Autosomal dominant thrombocytopenia is most frequently a heterozygous Bernard–Soulier syndrome. Blood 97:1330–1335PubMedCrossRefGoogle Scholar
  73. Savoia A, Dufour C, Locatelli F, Noris P, Ambaglio C, Rosti V, Zecca M, Ferrari S, di Bari F, Corcione A, Di Stazio M, Seri M, Balduini CL (2007) Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations. Hematologica 92:1186–1193CrossRefGoogle Scholar
  74. Savoia A, Noris P, Perrotta S, Punzo F, Rocco DD, Oostra BA, Balduini CL (2009) Absence of CYCS mutations in a large Italian cohort of patients with inherited thrombocytopenias of unknown origin. Platelets 20:72–73PubMedCrossRefGoogle Scholar
  75. Savoia A, De Rocco D, Panza E, Bozzi V, Scandellari R, Loffredo G, Mumford A, Heller PG, Noris P, De Groot MR, Giani M, Freddi P, Scognamiglio F, Riondino S, Pujol-Moix N, Fabris F, Seri M, Balduini CL, Pecci A (2010) MYH9-related disease (MYH9-RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder. Throm Haemost 103:826–832Google Scholar
  76. Savoia A, Pastore A, De Rocco D, Civaschi E, Di Stazio M, Bottega R, Melazzini F, Bozzi V, Pecci A, Magrin S, Balduini CL, Noris P (2011) Clinical and genetic aspects of Bernard–Soulier syndrome: searching for genotype/phenotype correlations. Haematologica 96:417–423PubMedCrossRefGoogle Scholar
  77. Schwer HD, Lecine P, Tiwari S, Italiano JE Jr, Hartwig JH, Shivdasani RA (2001) A lineage-restricted and divergent beta-tubulin isoform is essential for the biogenesis, structure and function of blood platelets. Curr Biol 11:579–586PubMedCrossRefGoogle Scholar
  78. Seri M, Pecci A, Di Bari F, Cusano M, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzarro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Soriano JR, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A (2003) MYH9-related disease: May–Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine 82:203–215PubMedGoogle Scholar
  79. Somerville C, Forsyth KD (1993) Wiskott–Aldrich syndrome: an immunodeficiency syndrome not rare in Western Australia. Pediatr Allergy Immunol 4:65–72PubMedCrossRefGoogle Scholar
  80. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23:166–175PubMedCrossRefGoogle Scholar
  81. Su Y, Wang Z, Yang H, Cao L, Liu F, Bai X, Ruan C (2006) Clinical and molecular genetic analysis of a family with sitosterolemia and co-existing erythrocyte and platelet abnormalities. Haematologica 91:1392–1395PubMedGoogle Scholar
  82. Thompson AA, Nguyen LT (2000) Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet 26:397–398PubMedCrossRefGoogle Scholar
  83. Thompson AR, Wood WG, Stamatoyannopoulos G (2007) X-linked syndrome of platelet dysfunction, thrombocytopenia, and imbalanced globin chain synthesis with hemolysis. Blood 50:303–316Google Scholar
  84. Van Zutven LJ, van Bever Y, Van Nieuwland CC, Huijbregts GC, Van Opstal D, von Bergh AR, Corel LJ, Tibboel D, Wouters CH, Poddighe PJ (2009) Interstitial 11q deletion derived from a maternal ins(4;11)(p14;q24.2q25): a patient report and review. Am J Med Genet A 149A:1468–1475PubMedCrossRefGoogle Scholar
  85. Vettore S, Scandellari R, Moro S, Lombardi AM, Scapin M, Randi ML, Fabris F (2008) Novel point mutation in a leucine-rich repeat of the GPIbalpha chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard–Soulier syndrome affecting two unrelated families: the N41H variant. Haematologica 93:1743–1747PubMedCrossRefGoogle Scholar
  86. Villa A, Notarangelo L, Macchi P, Mantuano E, Cavagni G, Brugnoni D, Strina D, Patrosso MC, Ramenghi U, Sacco MG et al (1995) X-linked thrombocytopenia and Wiskott–Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet 9:414–417PubMedCrossRefGoogle Scholar
  87. Wang G, Cao L, Wang Z, Jiang M, Sun X, Bai X, Ruan C (2012) Macrothrombocytopenia/stomatocytosis specially associated with phytosteria. Clin Appl Thromb Hemost. 2012 Jan 31. [Epub ahead of print]Google Scholar
  88. Weiss HJ, Meyer D, Rabinowitz R, Pietu G, Girma JP, Vicic WJ, Rogers J (1982) Pseudo-von Willebrand’s disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers. N Engl J Med 306:326–333PubMedCrossRefGoogle Scholar
  89. Wiskott A (1937) Familiärer, angeborener MorbusWerlhofii? Montasschr Kinderheilkd 68:212–216Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Pavia-IRCCS Policlinico San Matteo FoundationPaviaItaly
  2. 2.Laboratory of Genetics, Institute for Maternal and Child HealthUniversity of Trieste-IRCCS “Burlo Garofolo”TriesteItaly
  3. 3.Clinica Medica IIIFondazione IRCCS Policlinico San Matteo Piazzale GolgiPaviaItaly

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