PDF herunterladen
Semin Thromb Hemost 2011; 37(6): 673-681
DOI: 10.1055/s-0031-1291377
© Thieme Medical Publishers

Congenital Amegakaryocytic Thrombocytopenia: Clinical Presentation, Diagnosis, and Treatment

Matthias Ballmaier1 , Manuela Germeshausen1
  • 1Department of Pediatric Hematology and Oncology/Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
18. November 2011 (online)

    Lizenzen und Reprints

ABSTRACT

Congenital amegakaryocytic thrombocytopenia (CAMT, MIM #604498) is a rare inherited bone marrow failure syndrome presenting as isolated hypomegakaryocytic thrombocytopenia at birth without other characteristic physical anomalies. Most of the patients develop a severe aplastic anemia and trilineage cytopenia during the first years of life and hematopoietic stem cell transplantation is the only curative treatment. In most of the cases the disease is caused by homozygous or compound heterozygous mutations in the gene MPL encoding the receptor for the hematopoietic growth factor thrombopoietin. The present review summarizes clinical and laboratory data for 96 patients with CAMT, reported since 1990.

KEYWORDS

Bone marrow failure - thrombopoietin - MPL gene - hematopoietic stem cell transplantation - thrombocytopenia

REFERENCES

  • 1 Online Mendelian Inheritance in Man . Amegakaryocytic thrombocytopenia, congenital; CAMT.  http://www.ncbi.nlm.nih.gov/omim/604498 (Feb 25, 2011)
    Google Scholar
  • 2 Ihara K, Ishii E, Eguchi M et al.. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia.  Proc Natl Acad Sci U S A. 1999;  96 (6) 3132-3136
    Google Scholar
  • 3 Ballmaier M, Germeshausen M, Schulze H et al.. c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia.  Blood. 2001;  97 (1) 139-146
    Google Scholar
  • 4 Kaushansky K. Thrombopoietin: the primary regulator of platelet production.  Blood. 1995;  86 (2) 419-431
    Google Scholar
  • 5 Ballmaier M, Germeshausen M. Advances in the understanding of congenital amegakaryocytic thrombocytopenia.  Br J Haematol. 2009;  146 (1) 3-16
    Google Scholar
  • 6 Auerbach A D. A test for Fanconi's anemia.  Blood. 1988;  72 (1) 366-367
    Google Scholar
  • 7 Freedman M H. Congenital Marrow Failure Syndromes and Malignant Hematopoietic Transformation.  Oncologist. 1996;  1 (6) 354-360
    Google Scholar
  • 8 Guinan E C, Lee Y S, Lopez K D et al.. Effects of interleukin-3 and granulocyte-macrophage colony-stimulating factor on thrombopoiesis in congenital amegakaryocytic thrombocytopenia.  Blood. 1993;  81 (7) 1691-1698
    Google Scholar
  • 9 Muraoka K, Ishii E, Tsuji K et al.. Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia.  Br J Haematol. 1997;  96 (2) 287-292
    Google Scholar
  • 10 Henter J I, Winiarski J, Ljungman P, Ringdén O, Ost A. Bone marrow transplantation in two children with congenital amegakaryocytic thrombocytopenia.  Bone Marrow Transplant. 1995;  15 (5) 799-801
    Google Scholar
  • 11 Muraoka K, Ishii E, Ihara K et al.. Successful bone marrow transplantation in a patient with c-mpl-mutated congenital amegakaryocytic thrombocytopenia from a carrier donor.  Pediatr Transplant. 2005;  9 (1) 101-103
    Google Scholar
  • 12 MacMillan M L, Davies S M, Wagner J E, Ramsay N K. Engraftment of unrelated donor stem cells in children with familial amegakaryocytic thrombocytopenia.  Bone Marrow Transplant. 1998;  21 (7) 735-737
    Google Scholar
  • 13 Guinan E C, Boussiotis V A, Neuberg D et al.. Transplantation of anergic histoincompatible bone marrow allografts.  N Engl J Med. 1999;  340 (22) 1704-1714
    Google Scholar
  • 14 Lackner A, Basu O, Bierings M et al.. Haematopoietic stem cell transplantation for amegakaryocytic thrombocytopenia.  Br J Haematol. 2000;  109 (4) 773-775
    Google Scholar
  • 15 van den Oudenrijn S, Bruin M, Folman C C et al.. Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia.  Br J Haematol. 2000;  110 (2) 441-448
    Google Scholar
  • 16 van den Oudenrijn S, de Haas M, von dem Borne A E. Screening for c-mpl mutations in patients with congenital amegakaryocytic thrombocytopenia identifies a polymorphism.  Blood. 2001;  97 (11) 3675-3676
    Google Scholar
  • 17 van den Oudenrijn S, Bruin M, Folman C C, Bussel J, de Haas M, von dem Borne A E. Three parameters, plasma thrombopoietin levels, plasma glycocalicin levels and megakaryocyte culture, distinguish between different causes of congenital thrombocytopenia.  Br J Haematol. 2002;  117 (2) 390-398
    Google Scholar
  • 18 King S, Germeshausen M, Strauss G, Welte K, Ballmaier M. Congenital amegakaryocytic thrombocytopenia: a retrospective clinical analysis of 20 patients.  Br J Haematol. 2005;  131 (5) 636-644
    Google Scholar
  • 19 Germeshausen M, Ballmaier M, Welte K. MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: the type of mutation predicts the course of the disease.  Hum Mutat. 2006;  27 (3) 296
    Google Scholar
  • 20 Yeşilipek H V, Hazar V, Küpesiz A, Yegin O. Peripheral stem cell transplantation in a child with amegakaryocytic thrombocytopenia.  Bone Marrow Transplant. 2000;  26 (5) 571-572
    Google Scholar
  • 21 Kudo K, Kato K, Matsuyama T, Kojima S. Successful engraftment of unrelated donor stem cells in two children with congenital amegakaryocytic thrombocytopenia.  J Pediatr Hematol Oncol. 2002;  24 (1) 79-80
    Google Scholar
  • 22 Al-Ahmari A, Ayas M, Al-Jefri A, Al-Mahr M, Rifai S, El-Solh H. Allogeneic stem cell transplantation for patients with congenital amegakaryocytic thrombocytopenia (CAT).  Bone Marrow Transplant. 2004;  33 (8) 829-831
    Google Scholar
  • 23 Steele M, Hitzler J, Doyle J J et al.. Reduced intensity hematopoietic stem-cell transplantation across human leukocyte antigen barriers in a patient with congenital amegakaryocytic thrombocytopenia and monosomy 7.  Pediatr Blood Cancer. 2005;  45 (2) 212-216
    Google Scholar
  • 24 Gandhi M J, Pendergrass T W, Cummings C C, Ihara K, Blau C A, Drachman J G. Congenital amegakaryocytic thrombocytopenia in three siblings: molecular analysis of atypical clinical presentation.  Exp Hematol. 2005;  33 (10) 1215-1221
    Google Scholar
  • 25 Passos-Coelho J L, Sebastião M, Gameiro P et al.. Congenital amegakaryocytic thrombocytopenia—report of a new c-mpl gene missense mutation.  Am J Hematol. 2007;  82 (3) 240-241
    Google Scholar
  • 26 Pemberton L C, Levett D, Skinner R, Hall A G, Hanley J P. Novel mutations in a child with congenital amegakaryocytic thrombocytopenia.  Br J Haematol. 2006;  135 (5) 742-743
    Google Scholar
  • 27 Savoia A, Dufour C, Locatelli F et al.. Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations.  Haematologica. 2007;  92 (9) 1186-1193
    Google Scholar
  • 28 Tonelli R, Scardovi A L, Pession A et al.. Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT).  Hum Genet. 2000;  107 (3) 225-233
    Google Scholar
  • 29 Maserati E, Panarello C, Morerio C et al.. Clonal chromosome anomalies and propensity to myeloid malignancies in congenital amegakaryocytic thrombocytopenia (OMIM 604498).  Haematologica. 2008;  93 (8) 1271-1273
    Google Scholar
  • 30 Desai S R, Ranade S R. Congenital amegakaryocytic thrombocytopenia (CAMT): a case report with review of literature.  Indian J Pathol Microbiol. 2007;  50 (3) 659-660
    Google Scholar
  • 31 Steinberg O, Gilad G, Dgany O et al.. Congenital amegakaryocytic thrombocytopenia-3 novel c-MPL mutations and their phenotypic correlations.  J Pediatr Hematol Oncol. 2007;  29 (12) 822-825
    Google Scholar
  • 32 Tamary H, Nishri D, Yacobovich J et al.. Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry.  Haematologica. 2010;  95 (8) 1300-1307
    Google Scholar
  • 33 Bastida Eizaguirre M, Pereda Vicandi A, Pujana Zaldegui I. [Congenital amegakaryocytic thrombocytopenia in a 12 year old boy with no signs of pancytopenia: molecular analysis].  An Pediatr (Barc). 2008;  68 (4) 353-356
    Google Scholar
  • 34 Kanaji S, Kanaji T, Migita M et al.. Characterization of a patient with atypical amegakaryocytic thrombocytopenia.  Eur J Haematol. 2008;  80 (4) 361-364
    Google Scholar
  • 35 Fox N E, Chen R, Hitchcock I, Keates-Baleeiro J, Frangoul H, Geddis A E. Compound heterozygous c-Mpl mutations in a child with congenital amegakaryocytic thrombocytopenia: functional characterization and a review of the literature.  Exp Hematol. 2009;  37 (4) 495-503
    Google Scholar
  • 36 Rose M J, Nicol K K, Skeens M A, Gross T G, Kerlin B A. Congenital amegakaryocytic thrombocytopenia: the diagnostic importance of combining pathology with molecular genetics.  Pediatr Blood Cancer. 2008;  50 (6) 1263-1265
    Google Scholar
  • 37 Frangoul H, Keates-Baleeiro J, Calder C et al.. Unrelated bone marrow transplant for congenital amegakaryocytic thrombocytopenia: report of two cases and review of the literature.  Pediatr Transplant. 2010;  14 (4) E42-E45
    Google Scholar
  • 38 Chung H S, Koh K N, Kim H J et al.. A novel nonsense mutation in the MPL gene in congenital amegakaryocytic thrombocytopenia.  Pediatr Blood Cancer. 2011;  56 (2) 304-306
    Google Scholar
  • 39 Conde N, Quintero A E, Rives S et al.. Congenital amegakaryocytic thrombocytopenia (CAMT): a difficult early diagnosis.  Haematologica. 2010;  95 (Suppl 2) 412-413
    Google Scholar
  • 40 Martinón-Torres N, Vázquez-Donsión M, Loidi L, Couselo J M. CAMT in a female with developmental delay, facial malformations and central nervous system anomalies.  Pediatr Blood Cancer. 2011;  56 (3) 452-453
    Google Scholar
  • 41 Poles A, Keen L, Steward C et al.. Identification of mutations in the C-MPL gene confirms diagnosis of congenital amegakaryocytic thrombocytopenia (CAMT).  [abstract] Int J Immunogenet. 2010;  37 (5) 423
    Google Scholar
  • 42 Alter B P. Inherited bone marrow failure syndromes. In: Nathan D G, Stranahan R A, Orkin S H, Look A T, Ginsburg D, eds. Nathan and Oski's Hematology of Infancy and Childhood. 6th ed. Philadelphia: Saunders W.B.; 2003: 280-365
    Google Scholar
  • 43 Dame C, Wolber E M, Freitag P, Hofmann D, Bartmann P, Fandrey J. Thrombopoietin gene expression in the developing human central nervous system.  Brain Res Dev Brain Res. 2003;  143 (2) 217-223
    Google Scholar
  • 44 Ehrenreich H, Hasselblatt M, Knerlich F et al.. A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain.  Proc Natl Acad Sci U S A. 2005;  102 (3) 862-867
    Google Scholar
  • 45 Ivanova A, Wuerfel J, Zhang J, Hoffmann O, Ballmaier M, Dame C. Expression pattern of the thrombopoietin receptor (Mpl) in the murine central nervous system.  BMC Dev Biol. 2010;  10 77
    Google Scholar
  • 46 Hoffmann O, Rung O, Im A R et al.. Thrombopoietin contributes to neuronal damage in experimental bacterial meningitis.  Infect Immun. 2011;  79 (2) 928-936
    Google Scholar
  • 47 Khabbaze Y, Karayalcin G, Paley C, Shende A, Valderrama E, Lipton J M. Thrombocytopenia absent corpus callosum syndrome: third case of a distinct clinical entity.  J Pediatr Hematol Oncol. 2001;  23 (7) 469-471
    Google Scholar
  • 48 Knight S W, Heiss N S, Vulliamy T J et al.. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1.  Br J Haematol. 1999;  107 (2) 335-339
    Google Scholar
  • 49 Geddis A E. Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii.  Hematol Oncol Clin North Am. 2009;  23 (2) 321-331
    Google Scholar
  • 50 Souyri M, Vigon I, Penciolelli J-F, Heard J M, Tambourin P, Wendling F. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors.  Cell. 1990;  63 (6) 1137-1147
    Google Scholar
  • 51 Beer P A, Ortmann C A, Stegelmann F et al.. Molecular mechanisms associated with leukemic transformation of MPL-mutant myeloproliferative neoplasms.  Haematologica. 2010;  95 (12) 2153-2156
    Google Scholar
  • 52 Bagby G C, Meyers G. Bone marrow failure as a risk factor for clonal evolution: prospects for leukemia prevention.  Hematology (Am Soc Hematol Educ Program). 2007;  40-46
    Google Scholar
  • 53 Roberts I, Stanworth S, Murray N A. Thrombocytopenia in the neonate.  Blood Rev. 2008;  22 (4) 173-186
    Google Scholar
  • 54 Giampietro P F, Verlander P C, Davis J G, Auerbach A D. Diagnosis of Fanconi anemia in patients without congenital malformations: an international Fanconi Anemia Registry Study.  Am J Med Genet. 1997;  68 (1) 58-61
    Google Scholar
  • 55 Basel-Vanagaite L, Dokal I, Tamary H et al.. Expanding the clinical phenotype of autosomal dominant dyskeratosis congenita caused by TERT mutations.  Haematologica. 2008;  93 (6) 943-944
    Google Scholar
  • 56 Mehta P, Locatelli F, Stary J, Smith F O. Bone marrow transplantation for inherited bone marrow failure syndromes.  Pediatr Clin North Am. 2010;  57 (1) 147-170
    Google Scholar
  • 57 Shimamura A, Alter B P. Pathophysiology and management of inherited bone marrow failure syndromes.  Blood Rev. 2010;  24 (3) 101-122
    Google Scholar
  • 58 Bizzetto R, Bonfim C, Rocha V Eurocord and SAA-WP from EBMT et al. Outcomes after related and unrelated umbilical cord blood transplantation for hereditary bone marrow failure syndromes other than Fanconi anemia.  Haematologica. 2011;  96 (1) 134-141
    Google Scholar
  • 59 Cocault L, Bouscary D, Le Bousse Kerdiles C et al.. Ectopic expression of murine TPO receptor (c-mpl) in mice is pathogenic and induces erythroblastic proliferation.  Blood. 1996;  88 (5) 1656-1665
    Google Scholar
  • 60 Yan X Q, Lacey D L, Saris C et al.. Ectopic overexpression of c-mpl by retroviral-mediated gene transfer suppressed megakaryopoiesis but enhanced erythropoiesis in mice.  Exp Hematol. 1999;  27 (9) 1409-1417
    Google Scholar
  • 61 Wicke D C, Meyer J, Buesche G et al.. Gene therapy of MPL deficiency: challenging balance between leukemia and pancytopenia.  Mol Ther. 2010;  18 (2) 343-352
    Google Scholar
  • 62 Lannutti B J, Epp A, Roy J, Chen J, Josephson N C. Incomplete restoration of Mpl expression in the mpl-/- mouse produces partial correction of the stem cell-repopulating defect and paradoxical thrombocytosis.  Blood. 2009;  113 (8) 1778-1785
    Google Scholar
  • 63 Heckl D, Wicke D C, Brugman M H et al.. Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia.  Blood. 2011;  117 (14) 3737-3747
    Google Scholar

Matthias BallmaierPh.D. 

Pediatric Hematology and Oncology/Molecular Hematopoiesis, OE9411 - J11-H0-1110, Medizinische Hochschule Hannover

Carl-Neuberg- Strasse 1, D-30625 Hannover, Germany

eMail: Ballmaier.Matthias@mh-hannover.de

      >