Identification of a novel de novo deletion in RAF1 associated with biventricular hypertrophy in Noonan syndrome.

Biventricular hypertrophy (BVH) is a disease state characterized by the thickening of the ventricle walls. The differential diagnosis of BVH with other congenital and familial diseases in which increased ventricle wall thickness is a prominent clinical feature is fundamental due to its therapeutic and prognostic value, mainly during infancy. We describe a 2-month-old infant presenting BVH. Using exome sequencing, we identified a novel de novo 3-bp deletion in the RAF1 gene that is located in the binding active site for the 14-3-3 peptide. Based on docking calculations, we demonstrate that this novel mutation impairs protein/target binding, thus constitutively activating Ras signaling, which is a dysregulation associated with Noonan syndrome. Finally, our study underlines the importance of molecular modeling to understand the roles of novel mutations in pathogenesis.

The grown-up congenital cardiac patient.

Long-term survival of patients with congenital heart disease has dramatically improved during the last 50 years and the number of adults with congenital heart disease is therefore increasing in all developed countries. Grown-up patients with congenital heart disease (GUCH) often present difficult and challenging problems. Patients with both native unoperated and operated malformations contribute to the GUCH population. Survivors without surgical treatment mainly have simple malformations; but a few have complex diseases, and some have survived with secondary pulmonary hypertension. Among operated malformations there are patients with a 'complete' repair (anatomical and physiological), others with a definitive palliation (physiological repair) and some with a simple palliation. The clinical spectrum is obviously diversified, depending on the underlying anomaly, surgical outcome, presence of residua, sequelae and/or complications, length of follow-up, comorbidities. Arrhythmias, bacterial endocarditis, cyanosis, polycythemia, heart failure, anomalies of pulmonary circulation, deterioration or malfunction of devices, need of cardiac and non-cardiac surgery, intercurrent non-cardiac diseases, and a need for cardiac and non-cardiac diagnostic procedures are common problems of adults with congenital heart disease. Physiological events such as pregnancy and childbearing deserve a careful multidisciplinary approach. While most simple native and well corrected GUCH do not require very specialized treatments throughout their life, the abnormalities and complexities of postoperative anatomy are often beyond the expertise of the adult cardiologist, requiring multidisciplinary competence in specialized tertiary centers. The problem is still unresolved and involves cultural, medical, technological and economically relevant issues.

Clinical, anatomopathological and genetic pattern of 10 patients with cervical aortic arch.

Cervical aortic arch (CAA) is a rare congenital abnormality in which the aortic arch is situated cranially to its usual position, often associated with complex developmental alteration of aortic laterality and branching. More recently, some authors reported deletion of chromosome 22q11 (del22q11) in few patients with CAA. The aim of this study was to describe the clinical, anatomopathological and genetic pattern of 10 new cases of CAA. From 1975 to 2003, 10 patients with CAA (4 female, mean age 12.4+11.1 years) underwent complete cardiovascular evaluation and screening for del22q11 using fluorescence in situ hybridization. Six patients underwent CAA surgical repair with histological analysis of aorta samples. Six patients were asymptomatic; one patient had syncope on effort, 2 patients had dyspnea on effort and 1 had cyanosis and dyspnea (tricuspid atresia). A murmur and/or a pulsatile mass of the neck was present in all patients. Femoral pulses were weak or absent in 6 patients. Four patients had right and 6 left CAA; kinking or true obstruction of the aortic arch was present in 9/10. Abnormal aortic arch branching pattern was found in 8/10 (mainly aberrant subclavian artery). Two patients had del22q11 with dysmorphic features, multiorgan anomalies and degenerative mediocystic necrosis of aortic wall. Our data confirm clinical polymorphism and anatomic complexity of CAA as well as the association between del22q11 and CCA in 2 syndromic patients.