Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395

Management of the hypoplastic left heart syndrome : from fetus to adult

Non peer reviewe

Reference Ranges of Blood Flow in the Major Vessels of the Normal Human Fetal Circulation at Term by Phase-Contrast Magnetic Resonance Imaging

Background— Phase-contrast MRI with metric-optimized gating is a promising new technique for studying the distribution of the fetal circulation. However, mean and reference ranges for blood flow measurements made in the major fetal vessels using this technique are yet to be established. Methods and Results— We measured flow in the major vessels of the fetal circulation in 40 late-gestation normal human fetuses using phase-contrast MRI (mean gestational age, 37 [SD=1.1] weeks). Flows were indexed to the fetal weight, which was estimated from the fetal volume calculated by MRI segmentation. The following mean flows (in mL/min per kilogram; ±2SD) were obtained: combined ventricular output, 465 (351, 579); main pulmonary artery, 261 (169, 353); ascending aorta, 191 (121, 261); superior vena cava, 137 (77, 197); ductus arteriosus, 187 (109, 265); descending aorta, 252 (160, 344); pulmonary blood flow, 77 (0, 160); umbilical vein, 134 (62, 206); and foramen ovale, 135 (37, 233). Expressed as percentages of the combined ventricular output, the mean flows±2 SD were as follows: main pulmonary artery, 56 (44, 68); ascending aorta, 41 (29, 53); superior vena cava, 29 (15, 43); ductus arteriosus, 41 (25, 57); descending aorta, 55 (35, 75); pulmonary blood flow, 16 (0, 34); umbilical vein, 29 (11, 47); and foramen ovale, 29 (7, 51). A strong inverse relationship between foramen ovale shunt and pulmonary blood flow was noted ( r =−0.64; P &lt;0.0001). Conclusions— Although too small a sample size to provide normal ranges, these results are in keeping with those predicted in humans based on measurements made in fetal lambs using radioactive microspheres and provide preliminary reference ranges for the late-gestation human fetuses. The wide range we found in foramen ovale shunting suggests a degree of variability in the way blood is streamed through the fetal circulation. </jats:sec

Cardiac magnetic resonance imaging in congenital heart disease

Position paper of a group of Swiss paediatric and adult cardiologists, and radiologists performing cardiac magnetic resonance in congenital heart disease, endorsed by the working groups “Adult Congenital Heart Disease” (WATCH) and “Echocardiography and Cardiac Imaging” of the Swiss Society of Cardiology, the Swiss Society of Pediatric Cardiology and the Ressort Cardiac Imaging of the Swiss Society of Radiology