Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations.

Noonan syndrome is a genetic condition characterized by congenital heart defects, short stature, and characteristic facial features. Familial or de novo mutations in PTPN11, RAF1, SOS1, KRAS, and NRAS are responsible for 60-75% of the cases, thus, additional genes are expected to be involved in the pathogenesis. In addition, the genotype-phenotype correlation has been hindered by the highly variable expressivity of the disease. For all these reasons, expanding the genotyped and clinically evaluated case numbers will benefit the clinical community. A mutation analysis has been performed on RAF1, SOS1, and GRB2, in 24 patients previously found to be negative for PTPN11 and KRAS mutations. We identified four mutations in SOS1 and one in RAF1, while no GRB2 variants have been found. Interestingly, the RAF1 mutation was present in a patient also carrying a newly identified p.R497Q familial SOS1 mutation, segregating with a typical Noonan Syndrome SOS1 cutaneous phenotype. Functional analysis demonstrated that the R497Q SOS1 mutation leads to Jnk activation, but has no effect on the Ras effector Erk1. We propose that this variant might contribute to the onset of the peculiar ectodermal traits displayed by the propositus amidst the more classical Noonan syndrome presentation. To our knowledge, this is the first reported case of a patient harboring mutations in two genes, with an involvement of both Ras and Rac1 pathways, indicating that SOS1 may have a role of modifier gene that might contribute the variable expressivity of the disease, evidencing a genotype-phenotype correlation in the family.

The decision-making process in antibacterial treatment of pediatric upper respiratory infections: a national prospective office-based observational study.

BACKGROUND: The identification of patient management practices and the sources of medical information is crucial for rationalizing the treatment of respiratory tract infections, whose high incidence, especially in children, makes them one of the maior areas of unnecessary health expenditure. MATERIALS AND METHODS: This national prospective study was designed to investigate the diagnostic and prescribing habits of 100 office-based pediatricians managing upper respiratory tract infections in 1111 pediatric patients (604 males, mean age 6.7962.77 years; 507 females, mean age 6.7362.8 years) sequentially enrolled when an antibiotic treatment was deemed necessary. RESULTS: The most frequently diagnosed diseases were acute tonsillopharyngitis (56.2%) and acute otitis media (18.1%). Penicillins were prescribed in 34.3% of the cases, cephalosporins in 38.1%, and macrolides in 26.1%: oral drugs accounted for 92.2% of the prescriptions. The treatments were administered once or twice daily in 75.8% of the patients, and prescribed for 8 days in more than 80%; 76.7% also received supportive or symptomatic treatment (antipyretics, corticosteroids, cough suppressants and non-steroidal anti-inflammatory drugs). Laboratory or radiologic investigations were rarely requested. The main sources of medical information indicated by the participating pediatricians were pharmaceutical companies (35.6%) and meeting or congress reports (27.3%). CONCLUSIONS: The results indicate that more active education is still needed to improve the decision-making processes of office-based pediatricians.