MEK1 (Phospho-Thr286) ELISA Kit

Noonan syndrome with multiple giant cell lesions (NS/MGCL) was recently shown to be a phenotypic variation within the syndromes of the Ras/MAPK pathway and not an independent entity as previously thought. Here we report on a 13-year-old boy with a typical phenotype of NS including atrial septal defect, pulmonic stenosis, short stature, and combined pectus carinatum/excavatum, pronounced MGCL of both jaws, and a de novo mutation in PTPN11, c.236A>G (which predicts p.Q79R). Mutations in PTPN11 are the most frequent cause of NS and p.Q79R is a recurrent mutation in exon 3. Including this patient, 24 patients with molecularly confirmed NS, LEOPARD, or CFC/MGCL syndrome have been reported to date, of these 21 patients have PTPN11, SOS1, or RAF1 mutations and three have BRAF or MAP2K1 mutations, confirming that MGCL is a rare complication of the deregulated RAS/MAPK pathway. In all patients, the lesions of the mandible and to a lesser extent of the maxilla were first noted between ages 2 and 19 years (median 11 years), and were combined with enlargement of the jaws in 11/24 patients (46%). In this case and, with one exception (mutation not reported), all previous cases the NS/MGCL was caused by known mutations in the PTPN11, SOS1, RAF1, BRAF1, and MAP2K1 genes that were previously reported with RASopathies without MGCL. (C) 2012 Wiley Periodicals, Inc.

Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.