Identification of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: A possible explanation for divergent clinical behavior

Mastocytosis represents a mast cell proliferative disease that generally ru ns a benign clinical course, with spontaneous remissions mostly by puberty in childhood-onset disease, although rare forms, particularly in adult-onse t disease, can be associated with (pre)malignant hematologic disorders and very rarely present as mast cell leukemia of malignant mastocytosis, Reason s for this divergent clinical behavior of childhood- versus adult-onset dis ease are unknown. Recently, two activating mutations in the intracellular d omain of the proto-oncogene c-kit, which encodes a tyrosine kinase receptor for the mast cell growth factor stem cell factor, have been detected in th e human leukemic mast cell line HMC-1. We have therefore studied lesional s kin biopsies from patients with adult- and childhood-onset indolent mastocy tosis for the presence of these codon 560 and 816 mutations. C-kit coding D NA sequences were amplified and analyzed by mutation-specific restriction a nalyses, and mutated polymerase chain reaction products were additionally c loned and sequenced. The codon 816 mutation was found in all six samples fr om adult patients, but not in any of the 11 specimens from children. In add ition, the codon 560 mutation could be demonstrated for the first time in i ndolent mastocytosis, namely in two of four specimens from adult patients, but not in those from two children. These data thus provide a possible expl anation for the divergent clinical behavior of adult- versus childhood-onse t indolent mastocytosis, with the first being associated with an activating mutation, possibly as part of a neoplastic process, and the latter represe nting most likely a reactive process of an as yet unknown pathogenesis.