Gain-of-function mutations in Shp2, particularly those that reside within the N- or C-terminal SH2 domains that disrupt the closed, auto-inhibited conformation of the phosphatase, have been implicated in various cancers as well as in developmental disorders including NS and JMML (Bentires-Alj et al, 2004; Chan et al, 2009; Mohi and Neel, 2007). Here, PTPN11 is linked to juvenile myelomonocytic leukemia.