RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.

No abstract

Clinicians currently favour lower SpO2 targets for preterm resuscitation, despite acknowledging the lack of evidence for benefit or harm, and 65% would join a clinical trial.

Key words Cronobacter spp., Enterobacter sakazakii, extremely low birth weight infant, neonate, sepsis.Enterobacter sakazakii (Cronobacter spp.) is a rare but often fatal cause of neonatal infection. Powdered infant formula is recognized as the main source of this bacterium, but little is known about its ecology, taxonomy, virulence, and other characteristics. We encountered a case of fatal Enterobacter sakazakii (Cronobacter spp.) infection in a preterm neonate. To the best of our knowledge, this is the first fatal case in a neonate Japan. Clinicians in Japan are advised to be vigilant for this bacterium as a cause of fatal neonatal infection.

No abstract