Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations.

Noonan syndrome (NS) is an autosomal dominant disorder caused by mutations in PTPN11, KRAS, SOS1, and RAF1. We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients. Three novel SOS1 mutations were found. One was classified as a rare benign variant and the other remains unclassified. We confirm a high prevalence of pulmonic stenosis and ectodermal abnormalities in SOS1-positive patients. Three patients with SOS1 mutations presented with tumors (embryonal rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of the skin). One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor. This is the first report describing different tumor types in NS patients with germ line SOS1 mutations.

Multiomics Analysis Coupled with Text Mining Identify Novel Biomarker Candidates for Recurrent Cardiovascular Events.

Recurrent cardiovascular events remain an enigma that accounts for >30% of deaths worldwide. While heredity and human genetics variation play a key role, host-environment interactions offer a sound conceptual framework to dissect the molecular basis of recurrent cardiovascular events from genes and proteins to metabolites, thus accounting for environmental contributions as well. We report here a multiomics systems science approach so as to map interindividual variability in susceptibility to recurrent cardiovascular events. First, we performed data and text mining through a mixed-methods content analysis to select genomic variants, 10 single nucleotide polymorphisms, and microRNAs (miR-10a, miR-21, and miR-20a), minimizing bias in candidate marker selection. Next, we validated our in silico data in a patient cohort suffering from recurrent cardiovascular events (a cross-sectional study design and sampling). Our findings report a key role in low-density lipoprotein clearance for rs11206510 (p < 0.01) and rs515135 (p < 0.05). miR-10a (p < 0.05) was significantly associated with heart failure, while increased expression levels for miR-21 and miR-20a associated with atherosclerosis. In addition, liquid chromatography-mass spectrometry-based (LC-MS-based) proteomics analyses identified that vascular diameter and cholesterol levels are among the key factors to be considered in recurrent cardiovascular events. From a methodology innovation standpoint, this study offers a strategy to enhance the signal-to-noise ratios in mapping novel biomarker candidates wherein each research and conceptual step were interrogated for their validity and in turn, enriched one another, ideally translating information growth to knowledge growth.

Three novel mutations in greek sotos patients with rare clinical manifestations.

BACKGROUND: Sotos syndrome is an autosomal dominant disease characterized by tall stature, advanced bone age, typical morphological abnormalities of the face and developmental delay. It is caused by mutations in the NSD1 gene located on chromosome 5. NSD1 mutations are detected in the majority of the Sotos patients, and include intragenic NSD1 mutations and microdeletions in the 5q35 region. Cardiovascular and urogenital symptoms are more frequent in the microdeletion group. METHODS: Mutation analysis was performed in 4 patients with Sotos syndrome with typical phenotypic characteristics. RESULTS: In each of the 4 patients a NSD1 mutation was found (2 frame shifts, 1 nonsense and 1 missense mutation). Two of our patients presented dysplastic kidneys with cysts and psychosis, respectively. CONCLUSIONS: We describe 4 Greek patients with Sotos syndrome. Apart from the typical phenotypic characteristics, 2 of our patients presented rare clinical manifestations such as dysplastic kidneys and psychosis. The 3 detected mutations are novel.

Tumor development in three patients with Noonan syndrome.

The diagnosis of Noonan syndrome is essentially clinical, based upon the distinct phenotype and the involvement of the cardiovascular system. Tumor development is a rare manifestation of Noonan syndrome but can be explained by the molecular pathophysiology involved in the disorder. We present three Noonan patients who developed solid tumors. The first patient, a 4-year-old girl, developed granular cell tumors as did her mother in childhood. The second patient, a 1-year-old boy, had a low grade pilocytic astrocytoma, the clinical expression of which was persistent headache. MRI showed a pituitary mass in the posterior lobe. It was surgically removed. The third patient, a 7-year-old boy was found to have Sertoli tumors in his right cryptorchid testis. All three patients fulfilled the clinical criteria for Noonan syndrome. However, genetic testing was negative in patients 1 and 3. The diagnosis of Noonan syndrome was made based on distinct phenotypic findings in three patients who had different types of tumors.

Inflammation and chronic heart failure: from biomarkers to novel anti-inflammatory therapeutic strategies.

Heart failure (HF) is a complex heterogeneous syndrome with immune, metabolic and neurohumoral mechanisms interacting and leading to gradual heart contractility impairment. From the first study-to correlate inflammation with HF, inflammation biomarkers have been the subject of intense inquiry in patients with various forms of HF. Chronic HF (CHF) is strongly associated with inflammation in terms of pathogenesis, progression, severity and prognosis. Inflammatory mediators participate in CHF pathophysiology in various ways like exerting direct impact on cardiac myocytes, fibroblasts and ß-adrenergic receptors leading to hypertrophy, fibrosis and impaired cardiac contractility, respectively, or inducing apoptosis by stimulation of the proper genes. The anti-inflammatory effects of classical heart failure therapeutic strategies such as ACEI and b-blockers are rather conflicting. Whether novel immunomodulating and anti-inflammatory therapeutic approaches should be added to existing therapies in order to ensure additional benefit to HF patients is under investigation. In this review, we summarize the pathophysiological link between inflammatory processes and CHF, focusing on the role of novel and traditional inflammatory biomarkers and highlighting novel anti-inflammatory therapeutic strategies.

A clinical study of Sotos syndrome patients with review of the literature.

Sotos syndrome is characterized by tall stature, advanced bone age, typical facial abnormalities, and developmental delay. The associated gene is NSD1. The study involved 22 patients who fulfilled the clinical criteria. Phenotypic characteristics, central nervous system findings, and cardiovascular and urinary tract abnormalities were evaluated. Meta-analysis on the incidence of cardinal clinical manifestations from the literature was also performed. Macrocephaly was present in all patients. Advanced bone age was noted in 14 of 22 patients (63%), and its incidence presented significant statistical difference in the meta-analysis of previous studies. Some patients had serious clinical manifestations, such as congenital heart defects, dysplastic kidneys, psychosis, and leukemia. Clinical and laboratory examinations should be performed to prevent and manage any unusual medical aspect of the syndrome. Facial gestalt and macrocephaly, rather than advanced bone age, are the strongest indications for clinical diagnosis.