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Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies». Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches., (Copyright © 2020 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Molecular characterization of congenital heart diseases now includes the not infrequent dysmorphic Noonan syndrome. A study of 6 genes of the RAS-MAPK pathway in Spanish patients is presented: the impact of heart disease, clinical expressivity, and diagnostic yield are investigated., Methods: The study included 643 patients (and 182 family members) diagnosed by dysmorphologists, cardiologists, and pediatric endocrinologists from 74 tertiary hospitals. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, KRAS and HRAS focused on exons carrying recurrent mutations accounting for 80% to 95% of previously described mutations., Results: Mutations were detected in 230 patients (91 women and 139 men) in 200 (31%) families (172 PTPN11+, 14 SOS1+, 9 RAF1+, 5 BRAF+). There was specific reference to the heart defect suffered in 156 index cases: 103 patients had shown pulmonary stenosis, 12 pulmonary stenosis with hyperthrophic cardiomyopathy, 18 hypertrophic cardiomiopathy, and 14 other cardiopathies; heart disease was absent in 9 index cases. Heart disease had not been documented in 23 of 30 family members with positive genotype and compatible clinical signs. Diagnostic yield was higher (P=.016) for samples from some centers (53%; 14/32) and even from certain professionals (64%; 9/14; P=.019). Characterization rate was 18% in patients for whom clinical data were not available. Genotyping led to a more precise diagnosis in 26 patients., Conclusions: Most patients (94%) with a positive genotype had known congenital heart disease, 79% pulmonary stenosis and 12% hyperthrophic cardiomyopathy. Cardiopathy had not been documented in 76% of family members carrying the mutation. Molecular study is a useful tool in these syndromes but a more rigorous clinical diagnosis should be intended as well., (Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

A number of molecular alterations have been described for melanoma. Melanomas with BRAF mutations tend to be located in areas of intermittent sun exposure, whereas melanomas with KIT mutations mostly appear in acral areas, the mucosas, and areas of chronic sun exposure. Sorafenib, a BRAF inhibitor, has a cytostatic effect on most melanomas with mutations affecting the mitogen-activated protein kinase (MAPK) pathway, and is also capable of triggering apoptosis in a small subgroup of these melanomas. By inhibiting KIT, imatinib has a cytostatic and cytotoxic effect on melanomas with KIT mutations, and probably has the same effect on another subgroup of melanomas with other as yet imperfectly understood KIT mutations. For therapy to be effective, agents should be selected according to the pathways associated with the genetic mutations present in the melanoma.