c-kit Mutations in patients with childhood-onset mastocytosis and genotype-phenotype correlation

Mastocytosis represents a clonal proliferation of mast cell hematopoietic progenitors caused by gain-of-function mutations of the c-kit gene. The heterogeneity of c-kit mutations may have contributed to difficulties in characterizing genotype-phenotype correlation of the disease. Our goal was to analyze a set of reported pathogenic c-kit mutations in patients with childhood-onset cutaneous mastocytosis, in comparison with those with adult-onset disease, and to correlate these with clinical presentation. We performed polymerase chain reaction and direct sequencing using genomic DNA samples from 16 nonfamilial Japanese patients with indolent cutaneous mastocytosis (12 with childhood-onset disease and 4 with adult-onset disease) to look for the most common c-kit mutations at codons 816, 560, 820, and 839. A substantial number of patients had missense codon 816 mutations (10 of 12 in the childhood-onset group, 83.3%; and 4 of 4 in the adult-onset group, 100%). The most common mutation was Asp816Val (9 of 16, 64.3%) followed by Asp816Phe (5 of 16, 35.7%). Moreover, children with the Asp816Phe mutation developed cutaneous mastocytosis at an earlier age as compared to those with the Asp816Val mutation (mean age of onset, 1.3 months versus 5.9 months, respectively; P = 0.068). No other mutation variations were found in our cohort. In summary, we confirmed a high incidence of two distinct c-kit mutations, Asp816Val and Asp816Phe, in patients with childhood-onset cutaneous mastocytosis. Our results provide new insights into common c-kit mutations, which may contribute to different clinical courses of the disease.