Rosai-Dorman-Disease is one subgroup of Non-Langerhans cell histiocytosis with massive lymphadenopathy. It is a generally a benign and self-limiting disease, but an association to hemato-lymphoid malignancies or immune diseases is suspected. We present the case of a 6-year old male patient with multifocal extranodal RDD developing a secondary biphenotypic, treatment-resistant leukemia during treatment. Hypothysing that RDD and the secondary leukemia could be based on the same malign clone or on a cancer predispostion syndrome, whole-exome-sequencing of a saliva sample and leukemic cells were performed. A common marker of cell lines of histiocytosis and leukemic blasts has not been found.