Pediatric Mastocytosis Is a Clonal Disease Associated with D816V and Other Activating c-KIT Mutations

Abstract

Adult mastocytosis is an incurable clonal disease associated with c-KIT mutations, mostly in exon 17 (D816V). In contrast, pediatric mastocytosis often spontaneously regresses and is considered a reactive disease. Previous studies on childhood mastocytosis assessed only a few patients and focused primarily on codon 816 mutations, with various results. In this study, we analyzed the entire c-KIT sequence from cutaneous biopsies of 50 children with mastocytosis (ages 0-16 years). A mutation of codon 816 (exon 17) was found in 42% of cases, and mutations outside exon 17 were observed in 44%. Unexpectedly, half of the mutations were located in the fifth Ig loop of c-KIT's extracellular domain, which is encoded by exons 8 and 9. All mutations identified in this study were somatic and caused a constitutive activation of c-KIT. There was no clear phenotype-genotype correlation, no clear relationship between the mutations and familial versus spontaneous disease, and no significant change in the relative expression of the c-KIT GNNK+ and GNNK isoforms. These findings strongly support the idea that, although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with activating mutations in c-KIT.

Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage

“…In initial sequencing studies no KIT point mutation at codon 816, the most frequent codon affected in SM [22,23,[27][28][29] could be detected. In a next step, we sequenced all exons of KIT including hot-spot regions where point mutations are expected to occur (exons 5, 9, 10 and 17) [4,29,30]. In these studies, the heterozygous point mutation KIT c.1427G>T, pS476I was detected in neoplastic cells (Supplementary Figure S1).…”

“…In about 50-80% of all patients with MCL, a KIT mutation can be detected [4,[26][27][28][29][30]. In a majority of all patients with SM, MCs express the recurrent KIT mutation D816V [26][27][28][29][30].…”

“…In a majority of all patients with SM, MCs express the recurrent KIT mutation D816V [26][27][28][29][30]. However, not all patients with MCL exhibit a KIT mutation at codon 816.…”

“…The KIT mutation S476I may provide growth-promoting, pro-oncogenic effects in neoplastic cells in vitro [30,32]. Therefore, we were interested to learn whether KITtargeting drugs can counteract growth of neoplastic MCs in our patient.…”

Anesthetic considerations in pediatric mastocytosis: a review

“…Fewer than one-half of adolescent cases progress into adulthood, where the course may become systemic in up to 30 % of affected children, usually as an indolent form [13,15,17,19]. It is unclear which disease subtype seen in adolescence will progress into the adult form of the disease [25]. All adult cases are assumed to be systemic until clinical evaluation proves otherwise [26].…”