Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations

Abstract

BACKGROUND AND OBJECTIVES: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. DESIGN AND METHODS: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. RESULTS: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-a and interferon-g was increased during pancytopenia as compared to in controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. INTERPRETATION AND CONCLUSIONS: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor

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

“…4,5 We report the cytogenetic investigations and the results of analysis by fluorescent in situ hybridization (FISH) on 5 unrelated Italian patients whose clinical characteristics and MPL gene mutations have already been reported.…”

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

“…The evolution of the disease in trilineage BM failure within the first years of life reflects the non-redundant role of TPO-R pathway in maintenance of the HSC compartment in postnatal life [17]. As a consequence of reduced clearance by Mks and platelets, plasma TPO levels of CAMT patients are exceedingly high [18,19]. Nonsense or frameshift MPL mutations always cause the complete loss of TPO-R through ablation of the entire intracellular domain.…”

Genetic panels in young patients with bone marrow failure: are they clinically relevant?

“…They included compound heterozygous mutations in FANCA, MPL, RTEL1, and SBDS with heterozygous mutations identified in GATA2, RUNX1, TERT, TINF2, and TP53. These have been reported to cause Fanconi anemia, 10 congenital amegakaryocytic thrombocytopenia, 8 dyskeratosis congenita, 7 and Shwachman-Diamond syndrome. 11 Additionally mutations in GATA2 and RUNX1 are known to have an inherited predisposition to leukemia and MDS.…”

“…The mutations identified for the 5 patients in the AA group included DKC1 (n=2), MPL (n=2), and TP53 (n=1). These all represent known constitutional mutations which have previously been described to result in the clinical syndromes of dyskeratosis congenita, 7 congenital amegakaryocytic thrombocytopenia, 8 and Li Fraumeni, 9 respectively.…”