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

2009; Elsevier BV; Volume: 130; Issue: 3 Linguagem: Inglês

10.1038/jid.2009.281

1523-1747

Christine Bodemer, Olivier Hermine, Fabienne Palmérini, Ying Yang, Catherine Grandpeix‐Guyodo, Phillip S. Leventhal, S. Hadj‐Rabia, Laurent Nasca, Sophie Georgin-Lavialle, Annick Cohen-Akenine, Jean-Marie Launay, Stéphane Barète, Frédéric Féger, Michel Arock, B. Catteau, B. Sans, J.F. Stalder, Francois Skowron, L. Thomas, G Lorette, P. Plantin, Pierre Bordigoni, Olivier Lortholary, Y. De Prost, Alain Moussy, Hagay Sobol, Patrice Dubreuil,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

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. JID JOURNAL CLUB ARTICLE: For questions and answers about this article, please go to http://www.nature.com/jid/journalclub 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. JID JOURNAL CLUB ARTICLE: For questions and answers about this article, please go to http://www.nature.com/jid/journalclub gastrointestinal stromal tumor internal tandem duplication stem cell factor wild type