Congenital amegakaryocytic thrombocytopenia: a retrospective clinical analysis of 20 patients

Abstract

Summary Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare bone marrow failure syndrome characterised by isolated thrombocytopenia because of ineffective megakaryocytopoiesis at birth. In the last 10 years, we collected data from 20 patients diagnosed with CAMT based on a severe thrombocytopenia since birth and absent or markedly decreased numbers of megakaryocytes in the bone marrow. Fanconi's anaemia and thrombocytopenia absent radii syndrome were ruled out for all patients. We retrospectively compared the clinical courses, laboratory findings and treatment outcome. Development of pancytopenia was observed in 14 of the patients, only one patient presented with an isolated thrombocytopenia over a period of over 14 years. One boy died from bleeding complications. We defined two groups of patients according to the course of platelet counts during the first year of life, which also differed in the course of development of pancytopenia. Physical anomalies in addition to haematopoiesis were found in a number of patients: two children presented with cardiac defects, six with growth abnormalities, and four with retardation of psychomotor development. Fifteen patients were treated with haematopoietic stem cell transplantation, four of whom died of transplantation‐related events.

Clonal chromosome anomalies and propensity to myeloid malignancies in congenital amegakaryocytic thrombocytopenia (OMIM 604498)

“…A risk of evolution into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has often been assumed for CAMT, but in a search for bona fide CAMT patients who developed MDS/AML, we found only 3 such cases in the literature, and none of these was proved to carry mutations of the MPL gene: they are one refractory anemia with excess of blasts (RAEB) reported by King et al, 2 and 2 cases mentioned by Alter, 6 a male with acute myelomonocytic leukemia (AMML) developed after an aplastic anemia phase, and a female with a pre-leukemic condition. These 2 latter cases were never reported in more detail, and were studied some decades ago.…”

Megakaryocyte development and platelet production

“…Multiple mutations, including non-sense, frame-shift, splice-site alteration, missense or amino-acid substitutions, have been identified. These mutations result in a total absence of the c-Mpl receptor or functionally defective TPO-binding and/or signalling (van den Oudenrijn et al, 2002) with the type of mutation predicting the course of disease (Fig 3A) (King et al, 2005;Germeshausen et al, 2006). Congenital amegakaryocytic thrombocytopenia type I BM failure syndrome (CAMT I) in children is characterised by persistently low platelet counts (<20 · 10 9 /l) and fast progression into pancytopenia (van den Oudenrijn et al, 2002).…”

Genetic Basis of Inherited Bone Marrow Failure Syndromes

“…Missense mutations which only partially reduce receptor signaling are associated with relatively milder initial phenotype and slow progression into pancytopenia. (King, Germeshausen et al 2005;Ballmaier and Germeshausen 2009) However, the overall outcome might not be different. (Ballmaier and Germeshausen 2009) …”

“…Biallelic mutations in the MPL (thrombopoietic receptor) gene are the cause for the disorder in 94% of the patients with CAMT, 26 particularly, (Ballmaier, Germeshausen et al 2001) but not exclusively, (King, Germeshausen et al 2005) (Dror, Unpublished Data) in those without physical anomalies. MPL mutations cause inactivation of the thrombopoietin receptor.…”

“…In untreated cases, MDS with monosomy 7 and AML can develop at a later stage. (Lau, Ha et al 1999) Non-hematological manifestations occur in about one fifth of the patients and include cardiac defects, growth abnormalities, psychomotor retardation (King, Germeshausen et al 2005) and brain structural malformations (Dror, Unpublished Data). The only curative treatment is HSCT and is indicated in patients who persistently manifest severe cytopenia.…”