title: Hereditary thrombocythemia caused by a thrombopoietin (THPO) gain-of-function mutation associated with multiple myeloma and congenital limb defects.
abstract: Hereditary thrombocythemia (HT) has been described as a rare benign disorder caused by mutations in the thrombopoietin (THPO) or the c-Mpl receptor genes. Here we report two families with HT resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3. In one family there were coexisting distal limb defects, whereas in the other one member developed early-onset multiple myeloma. These observations, together with previously reported patients, suggest that THPO gain of function may dysregulate the hemangioblast and disturb vasculogenesis and hematopoietic development. Overstimulation of the THPO pathway might therefore predispose to clonal hematopoietic disease and to congenital abnormalities.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Stockklausner
authors.forename: Nicole
authors.initials: N
authors.lastname: Echner
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Klotter
authors.forename: Ute
authors.initials: U
authors.lastname: Hegenbart
authors.forename: Peter
authors.initials: P
authors.lastname: Dreger
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D017880:Limb Deformities, Congenital / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D013922:Thrombocytosis / Q000150:complications / Q000235:genetics*; D013926:Thrombopoietin / Q000235:genetics* / Q000502:physiology
chemical_list: D013926:Thrombopoietin