Congenital Amegakaryocytic Thrombocytopenia (CAMT): A Detailed Clinical Analysis of 21 Cases Reveals Different Types of CAMT.

CAMT is a rare disease characterized by thrombocytopenia in infancy due to ineffective megakaryopoiesis. We retrospectively analyzed clinical parameters of 21 patients diagnosed with CAMT, characterized by severe thrombocytopenia at birth, normal bone marrow cellularity and severely reduced numbers of megakaryocytes. 18 children developed postnatal bleeding symptoms with a median platelet count of 21/nl. 2 children suffered from a postnatal cerebral bleeding and intrauterine cerebral bleeding was suspected in 4 more children. We observed differences in the course of disease: 12 children formed a homogeneous group regarding the hematological parameters. Their platelet counts remained on a very low level, bone marrow cellularity decreased during the first year of life and they developed severe aplastic anemia in early infancy (2 to 53 months). 7 children also presented with physical anomalies like strabismus (2), nystagmus (2), motor and mental retardation (2), growth retardation (2) and cardiac defects (2). In 5 of 7 patients the parents were cousins of first degree. Sequence analysis of the c-mpl gene in 5 children revealed nonsense mutations with a complete loss of the thrombopoietin receptor. This group we classified as CAMT Type I. In contrast, 6 children formed a more heterogeneous group with delayed bone marrow failure. Their platelet counts at birth were slightly increased compared to those of type I patients (median 35/nl). In all children the number of platelets rose during early infancy and achieved a median maximum of 132/nl. At a median age of 4 9/12 years (range 3 to 6 10/12years) 4 children developed aplastic anemia. In one girl bone marrow morphology revealed refractory anemia with excess blasts at the age of 7 1/12 years. She received two bone marrow transplantations (BMT) and finally died from acute myeloid leukemia. Another girl feels well at the age of 14 years without signs of pancytopenia. One girl presented with growth retardation and a second with a small apical ventricular septal defect. Sequence analysis in 3 children revealed different forms of amino acid exchanges in the extracellular domain of c-Mpl. This might correspond to a residual function of c-Mpl. This group we classified as CAMT Type II. Altogether 18 children received BMT. 3 patients with type II CAMT required a second BMT due to primary graft failure, secondary graft failure and relapse of MDS. BMT with a matched unrelated donor (MUD) was performed in 5 patients, all with a fatal outcome. 8 children died at a mean age of 4 2/12 years: 2 due to bleeding complications and 6 following BMT. We conclude, that c-Mpl deficiency is the main reason for CAMT and can be associated with described physical anomalies. As exemplified the prognosis for patients is poor. Clinical differences can be seen between a total lack and a residual function of the c-Mpl receptor. Besides CAMT due to c-Mpl deficiency the incidence of congenital forms of ineffective megakaryopoiesis was described for other diseases with no defects in the c-mpl gene. (e.g. CAMT with radio-ulnar synostosis, Hoyeraal-Hreidarsson-Syndrome). This heterogeneous group of diseases with normal c-Mpl function we classified as CAMT Type III. Further clinical studies have to be performed to understand the relationship between genotype and clinical phenotype in terms of bone marrow failure, leukemia development and overall survival to better predict the clinical outcome.