SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, SMAD6-deficiency has been associated with three distinctive human congenital... Show moreSMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, SMAD6-deficiency has been associated with three distinctive human congenital conditions, i.e., congenital heart diseases, including left ventricular obstruction and conotruncal defects, craniosynostosis and radioulnar synostosis. Intriguingly, a similar spectrum of heterozygous loss-of-function variants has been reported to cause these clinically distinct disorders without a genotype-phenotype correlation. Even identical nucleotide changes have been described in patients with either a cardiovascular phenotype, craniosynostosis or radioulnar synostosis. These findings suggest that the primary pathogenic variant alone cannot explain the resultant patient phenotype. In this review, we summarise clinical and (patho)genetic (dis)similarities between these three SMAD6-related conditions, compare published Madh6 mouse models, in which the importance and impact of the genetic background with respect to the observed phenotype is highlighted, and elaborate on the cellular key mechanisms orchestrated by SMAD6 in the development of these three discrete inherited disorders. In addition, we discuss future research needed to elucidate the pathogenetic mechanisms underlying these diseases in order to improve their molecular diagnosis, advance therapeutic strategies and facilitate counselling of patients and their families. Show less
To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type ... Show moreTo optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS-related height increase across populations. Height and weight data of individuals with MFS aged 0-21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype-phenotype relationships, FBN1 variant type was included as an independent variable in height-for-age and BMI-for-age models. MFS-related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height-for-age, BMI-for-age, and weight-for-height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1-HI variants were associated with taller height in both sexes, and decreased BMI in females (p-values <0.05). This Dutch MFS growth study broadens the notion that genetic background and MFS variant type (HI/DN) influence tall and slender stature in MFS. Show less
Heer, F. de; Kluin, J.; Elkhoury, G.; Jondeau, G.; Enriquez-Sarano, M.; Schafers, H.J.; ... ; Aortic Valve Repair Res Network In 2019
Objectives: Current national registries are lacking detailed pathology-driven analysis and long-term patients outcomes. The Heart Valve Society (HVS) aortic valve (AV) repair research network... Show moreObjectives: Current national registries are lacking detailed pathology-driven analysis and long-term patients outcomes. The Heart Valve Society (HVS) aortic valve (AV) repair research network started the Aortic Valve Insufficiency and ascending aorta Aneurysm InternATiOnal Registry (AVIATOR) to evaluate long-term patient outcomes of AV repair and replacement. The purpose of the current report is to describe the AVIATOR initiative and report in a descriptive manner the patients included.Methods: The AV repair research network includes surgeons, cardiologists, and scientists and established an online database compliant with the guidelines for reporting valve-related events. Prospective inclusion started from January 2013. Adult patients (18 years or older) who were operated on between 1995 and 2017 with complete procedural specification of the type of repair/replacement were selected for descriptive analysis.Results: Currently 58 centers from 17 countries include 4896 patients with 89% AV repair (n = 4379) versus 11% AV replacement (n = 517). AV repair was either isolated (28%), or associated with tubular/partial root replacement (22%) or valve-sparing root replacement (49%) with an in-hospital mortality of 0.5%, 1.7%, and 1.2%, respectively. AV replacement was either isolated (24%), associated with tubular/partial root replacement (17%) or root replacement (59%) with an in-hospital mortality of 1%, 2.6%, and 2.0%, respectively.Conclusions: The multicenter surgical AVIATOR registry, by applying uniform definitions, should provide a solid evidence base to evaluate the place of repair versus replacement on the basis of long-term patient outcomes. Obtaining data completeness and adequate representation of all surgery types remain challenging. Toward the near future AVIATOR-medical will start to study natural history, as will AVIATOR-kids, with a focus on pediatric disease. Show less
