RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype-phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.

Background: The treatment of Kawasaki disease patients who fail to respond to initial i.v. immunoglobulin (IVIG) therapy is controversial. The aim of the present study was to investigate the long-term efficacy of plasma exchange (PE) treatment for refractory Kawasaki disease. Methods: A total of 125 Kawasaki disease patients refractory to IVIG were treated with PE. Coronary artery lesions (CAL) before PE, in the acute period, and during the late period were examined retrospectively. Results: Residual sequelae requiring medical treatment occurred in six cases in the late period. The outcomes of treatment tended to be better when PE was begun in the early stage. Sequelae remained in 2.8% of patients in whom PE was initiated prior to day 9 after onset, and were present in 15% of patients in whom PE was started on or after day 10. The 105 patients whose coronary arteries were normal before PE had no sequelae (residual sequelae: 0%). Dilatation was present before PE in 14 patients, but remained in only two patients in the late period (residual sequelae, 14.3%). In four of the six patients in whom aneurysms had already formed before PE, the lesions had advanced into giant aneurysms, but in the other two patients they returned to the normal range (residual sequelae, 66.6%). Conclusions:The outcomes of PE for Kawasaki disease refractory to IVIG are favorable, and the effectiveness of this treatment is excellent, particularly if it is initiated before CAL arise.Key words coronary artery lesion, i.v. immunoglobulin, Kawasaki disease, plasma exchange, refractory Kawasaki disease.Through the establishment of a high-dose i.v. immunoglobulin (IVIG) protocol for Kawasaki disease, a high level of effectiveness can be achieved, 1 but between 10 and 15% of patients still fail to respond. 2Alternative treatments for patients refractory to IVIG have not yet been developed, and the approaches being tested vary greatly from institution to institution. Plasma exchange (PE) is a method with promising efficacy, but the number of facilities that perform it is limited, and few reports on outcomes have been published so far.3,4 In particular, there are no large-scale studies on the effects of PE on coronary artery lesions (CAL) in the late period.In the present study, we investigated the long-term efficacy of PE in IVIG-refractory Kawasaki disease patients. Methods DemographicsThe subjects were 125 children with Kawasaki disease (onset: between August 1994 and March 2007) who had been treated with PE because IVIG had proven ineffective. Those patients in whom steroids other than IVIG had been given before PE had been started were excluded from the study (two patients). One patient who had been pre-treated with infliximab was also excluded. One hundred and sixteen patients received their first IVIG treatment in 19 affiliated hospitals located close to each other. When a patient was judged to be refractory to IVIG, the patient was referred to one of the two hospitals (Yokohama City University Hospital and Yokohama City University Med...

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Polymorphisms in VKORC1 partially affected daily warfarin dosage requirements. VKORC1 genotype and height are the primary determinants influencing warfarin dosage in Japanese pediatric patients. Further studies with larger sample sizes are needed to confirm our results.