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Congenital amegakaryocytic thrombocytopenia
An isolated constitutional thrombocytopenia characterized by an isolated and severe decrease in the number of platelets and megakaryocytes during the first years of life that develops into bone marrow failure with pancytopenia later in childhood.
ORPHA:3319Classification level: Disorder
Congenital amegakaryocytic thrombocytopenia (CAMT) prevalence is unknown and less than 100 cases have been reported in the literature. In addition, the incidence may be underestimated due to difficult and inconsistent diagnosis of the disease.
CAMT manifests since birth, often in the first day or at least within the first month of life, with petechiae, purpura, and gastrointestinal, pulmonary or intracranial hemorrhage due to isolated thrombocytopenia and a near absence of megakaryocytes in the bone marrow. Two types of CAMT have been identified. Type I-CAMT is the severe form of the disease and is characterized by persistently low platelet counts and early progression (usually by the age of 2 years) to bone marrow aplasia associated with pancytopenia. Type II-CAMT is a milder form which presents with transient increase of platelet counts over 50x109/L during the first year of life and late (by the age of 3-6 years) or no development of pancytopenia. Cardiac defects (atrial and ventricular septal defects), abnormalities of the central nervous system (cerebral and cerebellar hypoplasia), and retardation of psychomotor development have occasionally been reported.
CAMT is due to mutations in the MPL gene (1p34) coding for Thrombopoietin (TPO) receptor (c-MPL), expressed in pluripotent hematopoietic stem cells and cells of the megakaryocyte lineage. The binding of TPO to c-MPL stimulates platelet and megakaryocyte production. Different types of mutations have been associated with different phenotypes. Nonsense mutations predicted to result in a complete loss of function of the TPO receptor lead to type I-CAMT, whereas missense mutations predicted to lead to a residual function of the receptor are associated with type II-CAMT. Cases with no defects in the MPL gene are referred to as type III-CAMT. Recently, a 21q22 deletion resulting in RUNX1 haploinsufficiency has been reported in a case of CAMT associated with various anomalies (growth retardation, hearing deficits, hernias, poor feeding).
Diagnosis is based on clinical signs, on the evidence by blood tests of thrombocytopenia (platelet count below 50x109/L) with a normal mean platelet volume and of highly elevated serum levels of TPO, and on the observation in a bone marrow aspirate of absent or very few megakaryocytes. Genetic testing can confirm the diagnosis.
The initial presentation of CAMT with isolated thrombocytopenia can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP), while the late pancytopenic phase is indistinguishable from aplastic anemia. Fanconi anemia, thrombocytopenia-absent radius (TAR), syndrome and Wiscott-Aldrich syndrome (WAS) should be also ruled out.
Prenatal diagnosis is possible for families in which the disease-causing mutation has been identified.
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is supportive, mainly consisting of multiple platelet transfusions. At present, hematopoietic stem cell transplantation (HSCT) is the only curative therapy.
Prognosis is poor and with supportive therapy, progression to full marrow failure (tri-linear marrow aplasia) occurs during the first years of life. 30% of patients with CAMT die due to bleeding complications before the HSCT and 20% due to the HSCT.