By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

An NF1 microdeletion is the single most commonly reported mutation in individuals with neurofibromatosis type 1 (NF1). Individuals with an NF1 microdeletion have, as a group, more neurofibromas at a younger age than the group of all individuals with NF1. We report that NF1 microdeletion individuals additionally have a substantially higher lifetime risk for the development of malignant peripheral nerve sheath tumors than individuals with NF1 who do not have an NF1 microdeletion. This should be taken into account in the medical follow-up of individuals with an NF1 microdeletion.

LEOPARD syndrome is an autosomal dominant disorder with multiple lentigines, congenital cardiac abnormalities, ocular hypertelorism, and retardation of growth. Deafness and genital abnormalities are less frequently found. We report a father and daughter and a third, unrelated patient with LEOPARD syndrome. Recently, missense mutations in the PTPN11 gene located in 12q24 were found to cause Noonan syndrome. All three cases of LEOPARD syndrome reported here have a Y279C mutation in the PTPN11 gene. We hypothesise that some PTPN11 mutations are associated with the typical Noonan syndrome phenotype and that other mutations, such as the Y279C mutation reported here, are associated with both the Noonan syndrome phenotype and with skin pigmentation anomalies, such as multiple lentigines or café au lait spots.

Regulation of RAS by ubiquitination: The protein LZTR1 is mutated in human cancers and developmental diseases. Work from two groups now converges to implicate the protein in regulating signaling by the small guanosine triphosphatase RAS. Steklov et al. showed that mice haploinsufficient for LZTR1 recapitulated aspects of the human disease Noonan syndrome. Their biochemical studies showed that LZTR1 associated with RAS. LZTR1 appears to function as an adaptor that promotes ubiquitination of RAS, thus inhibiting its signaling functions. Bigenzahn et al. found LZTR1 in a screen for proteins whose absence led to resistance to the tyrosine kinase inhibitors used to treat cancers caused by the BCR-ABL oncogene product. Their biochemical studies and genetic studies in fruitflies also showed that loss of LZTR1 led to increased activity of RAS and signaling through the mitogen-activated protein kinase pathway. Science , this issue p. 1177 , p. 1171

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.