Angeborene Makrothrombozytopenie bei einer Kombination funktioneller Polymorphismen im TUBB1-Gen

Although immune thrombocytopenia is a common cause for chronic thrombocytopenia in children and adolescents other disorders potentially associated with low platelet counts should be taken into consideration. The differential diagnosis includes both hematologic malignancies and inherited platelet disorders (IPDs). Macrothrombocytopenias, a subgroup of IPDs, may result from a defective expression of membrane proteins such as Bernard-Soulier syndrome and variant Glanzmann thrombasthenia, MYH9-related diseases (May-Hegglin, Sebastian platelet, Fechtner or Epstein syndrome) or less frequent defects of the cytoskeleton (1). Therefore, the microscopic evaluation of peripheral blood smears is an essential part of the diagnostic workup since automated analyzers do not recognize macrothrombocytes reliably (6). β1-tubulin is the major element of microtubules and exclusively expressed in mature megakaryocytes and platelets. It is required for normal platelet formation (1, 10, 12) and maintenance of platelet discoid shape (5, 13). The TUBB1 gene encoding β1-tubulin is localized on the long arm of chromosome 20 (MIM *612901). Autosomal dominantly inherited mutations in this gene lead to decreased expression of the protein and may result in mild to moderate thrombocytopenia with platelet counts between 60 and 120 x 109/l (ref. range 150–400 x 109/l) (4, 10). The under expression of β1-tubulin, caused by the TUBB1 missense mutation p.R318W, seems to be associated with an impaired microtubule assembly (7). Further, proplatelet formation and release of granule contents can be influenced by p.F260S, another missense mutation of the TUBB1 gene which may lead to a reduced stability of the thrombus and congenital macrothrombocytopenia as well (8). According to the Exome Aggregation Consortium (ExAc) seven SNPs with a minor allele frequency (MAF) of > 1% could have been identified in the TUBB1 gene so far. Although mice deficient in β1-tubulin have a prolonged bleeding time (13) no reports on a bleeding tendency in patients with defective or missing β1-tubulin could be found. For avoiding potential bleedings in the context of invasive procedures patients may prophylac