Congenital Amegakaryocytic Thrombocytopenia in a Thrombocytopenic Child Presenting without Amegakaryocytosis.

Congenital amegakaryocytic thrombocytopenia (CAMT) is an inherited bone marrow syndrome due mutation of the thrombopoietin receptor c-Mpl. Affected children present with thrombocytopenia at birth and absence or severe reduction of megakaryocytes in the bone marrow and usually progress to complete bone marrow failure within the first decade of life. Mutations of c-Mpl have been classified as either type I mutations, in which the receptor has lost all activity, or type II mutations, in which the receptor retains some degree of function. Clinically, type II patients have a slightly delayed onset of bone marrow failure (mean age 48 months) compared to type I patients (22 months). Here we describe a girl with CAMT who had a clinical course similar to patients with type I mutations but without marked amegakaryocytosis at onset. The patient was born with intracranial hemorrhage due to severe thrombocytopenia (platelets 17K), which was initially thought to be due to alloimmune thrombocytopenia because of consistent platelet antigen typing studies and because the child responded to transfusion with her mother’s platelets and not to random donor platelets. However, thrombocytopenia persisted and she did not respond to immune directed therapies such as IVIG, prednisone or Rituximab, and after 14 months of age she began to develop neutropenia and anemia and by 24 months she had progressed to severe aplastic anemia. Bone marrow evaluation at 3 months showed trileage hematopoiesis with only mildly decreased megakaryocytes although they were noted to be small with hypolobulated nuclei. By 6 months of age, however, megakaryocytes appeared mildly decreased but were morphologically unremarkable and the marrow showed increased hematogones. At 24 months, marrow cellularity had decreased to 5% of normal with frank amegakaryocytosis. Sequencing of c-Mpl revealed two heterozygous mutations, one at Arg102Pro in the extracellular domain and the other one resulting in a stop codon at amino acid 541 in the intracellular domain. Arg102Pro is the most commonly occurring mutation reported in CAMT and is generally associated with type II disease. 541Stop is the first mutation reported in exon 11 and results in truncation of the receptor shortly after the box 1 homology domain. Previous in vitro studies involving the murine homolog of this mutation, which is missing all but the proximal 28 amino acids of the intracellular domain, demonstrated that it does not signal in response to thrombopoietin. This case illustrates the variation in clinical phenotype that can be seen in CAMT and the importance of gene sequencing for accurate diagnosis.