Congenital amegakaryocytic thrombocytopenia-3 novel c-MPL mutations and their phenotypic correlations.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare bone marrow failure syndrome associated with thrombocytopenia and a tendency to progress to aplastic anemia. Mutations in the c-MPL gene encoding for thrombopoietin receptor have been identified in the majority of the patients. Previous studies suggest a genotype-phenotype correlation wherein the severity of the disease depends on the type of mutation present and residual thrombopoietin receptor activity. The present study describes the clinical and genetic findings on a series of 7 patients with CAMT, 3 of them siblings. The patients were homozygous for 5 mutations in the c-MPL gene, including 3 unique ones: c.212+5G>A, C76T, and G1162C. The clinical picture was variable; 1 patient who was homozygous for a nonsense mutation in exon 1 (C76T) developed infantile acute lymphoblastic leukemia, whereas patients who were homozygous for a splice-site mutation (c.212+5G>A) expressing both normal and mutated transcripts had a milder clinical course. As previously suggested, c-MPL mutation analysis in CAMT patients helps to predict the clinical course and to provide optimal therapy.