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The objective of this study was to compare midterm outcomes of aortic valve-replacing root replacement (AVR) and aortic valve-sparing root replacement (AVS) operations in patients with Marfan syndrome.Patients who met strict Ghent diagnostic criteria for Marfan syndrome and who underwent either AVR or AVS between March 1, 2005 and December 31, 2010 were enrolled in a 3-year follow-up prospective, multicenter, international registry study; the study was subsequently amended to include 20-year follow-up. Enrollees were followed clinically and echocardiographically.Of the 316 patients enrolled, 77 underwent AVR and 239 underwent AVS; 214 gave reconsent for 20-year follow-up. The median clinical follow-up time for surviving patients was 64 months (interquartile range, 42-66 months). Survival rates for the AVR and AVS groups were similar at 88.2% ± 4.4% and 95.0% ± 1.5%, respectively (P = .1). Propensity score-adjusted competing risk modeling showed associations between AVS and higher cumulative incidences of major adverse valve-related events, valve-related morbidity, combined structural valve deterioration and nonstructural valve dysfunction, and aortic regurgitation ≥2+ (all P .01). No differences were found for reintervention (P = .7), bleeding (P = .2), embolism (P = .3), or valve-related mortality (P = .8).Five years postoperatively, major adverse valve-related events and valve-related morbidity were more frequent after AVS than after AVR procedures, primarily because of more frequent aortic valve dysfunction. No between-group differences were found in rates of survival, valve-related mortality, reintervention on the aortic valve, or bleeding. We plan to follow this homogenous cohort for 20 years after aortic root replacement.

Background Loeys-Dietz syndrome (LDS) is a systemic connective tissue disease (CTD) associated with a predisposition for intestinal inflammation, food allergy, and failure to thrive, often necessitating nutritional supplementation via gastrostomy tube. Poor wound healing has also been observed in in some patients with CTD, potentially increasing the risk of surgical interventions. We undertook to determine the safety and efficacy of gastrostomy tube placement in this population. Methods We performed a retrospective cohort study of 10 LDS patients who had a total of 12 gastrostomy tubes placed. Results No procedural complications occurred, although one patient developed buried bumper syndrome in the near post-procedural time period and one patient had a small abscess at a surgical stitch. Most patients exhibited improvements in growth, with a median immediate improvement in BMI Z-score of 0.2 per month following the institution of gastrostomy tube feedings. Those with uncontrolled inflammation due to inflammatory bowel disease or eosinophilic gastrointestinal disease showed the least benefit and in some cases failed to demonstrate significant weight gain despite nutritional supplementation. Conclusions Gastrostomy tube placement (surgical or endoscopic) is a generally safe and a reasonable therapeutic option for patients with LDS despite their underlying CTD.

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-α 1 chain of collagen III. Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. We created 2 mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glycine substitutions analogous to those found in patients, and we showed that signaling abnormalities in the PLC/IP(3)/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal–regulated kinase) are major mediators of vascular pathology. Treatment with pharmacologic inhibitors of ERK1/2 or PKCβ prevented death due to spontaneous aortic rupture. Additionally, we found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, was rescued by attenuation of oxytocin and androgen signaling, respectively. Taken together, our results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.

Tremendous progress has been made in understanding the etiology, pathogenesis, and treatment of inherited vascular connective tissue disorders. While new insights regarding disease etiology and pathogenesis have informed patient counseling and care, there are numerous obstacles that need to be overcome in order to achieve the full promise of precision medicine. In this review, these issues will be discussed in the context of Marfan syndrome and Loeys-Dietz syndrome, with additional emphasis on the pioneering contributions made by Victor McKusick.

An asymptomatic 3-year-old with Loeys-Dietz Syndrome (LDS) followed for a small patent ductus arteriosus and dilated aorta was found to have a massive ductal aneurysm on routine surveillance cardiac magnetic resonance. The aneurysm was successfully resected. Serial advanced imaging tools are useful in surveillance, diagnosis, and management in patients with LDS.

Item does not contain fulltext Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA. Intriguingly, patients with craniosynostosis have also been reported to be explained molecularly by similar loss-of-function SMAD6 variants. While significantly reduced penetrance of craniosynostosis has been reported for the SMAD6 variants as such, near-complete penetrance is reached upon co-occurrence with a common BMP2 SNP risk allele. Here, we report on the results of a SMAD6-variant analysis in 473 unrelated non-syndromic TAA patients, of which the SMAD6-positive individuals were also studied for the presence of the BMP2 risk allele. Although only 14% of the TAA patients also presented BAV, all novel likely pathogenic SMAD6 variants (N = 7) were identified in BAV/TAA individuals, further establishing the role of SMAD6 variants to the aetiology of BAV/TAA and revealing limited contribution to TAA development in patients with a tricuspid aortic valve. Familial segregation studies confirmed reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity. None of our six BMP2+/SMAD6+ patients presented with craniosynostosis. Hence, the proposed digenic model for craniosynostosis was not supported in the presented BAV/TAA cohort, suggesting that additional factors are at play. Finally, our data provide improved insights into the clinical spectrum of SMAD6-related BAV/TAA and has important implications for molecular diagnostics.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting multiple organ systems, including bone.We defined the bone phenotype and clinical predictors of low bone density and fracture risk in 77 patients with LDS type 1 to type 5.Patients with LDS had dual-energy x-ray absorptiometry (DXA) Z-scores significantly 0, and 50% of children and 9% of adults had Z-scores-2. Sixty percent of patients had ≥1 fracture, and 24% of patients with spinal x-rays scans showed spinal compression fractures. Lower body mass index, asthma, male sex and eosinophilic gastrointestinal disease were correlated with lower DXA Z-scores. The count of 5 LDS-associated skeletal features (scoliosis, pes planus, arachnodactyly, spondylolisthesis, and camptodactyly) in patients with LDS was correlated with DXA Z-score. Adults with ≥1 skeletal features had DXA Z-scores significantly 0, and children with2 features had DXA Z-score significantly-2. Bone turnover markers suggest accelerated bone resorption. Data from 5 patients treated with bisphosphonates suggest a beneficial effect.All LDS types are associated with reduced bone density and increased risk of fracture, which may be due to increased bone resorption. Clinical features can predict a subgroup of patients at highest risk of low bone density and fracture risk.

BackgroundMarfan syndrome (MFS) is a connective tissue disorder characterised by complex aortic pathology and a high prevalence of obstructive sleep apnoea (OSA). OSA produces intrathoracic transmural stresses that may accelerate aortic injury. The current study was designed to examine the associations between OSA risk and markers of aortic enlargement in MFS.MethodConsecutive patients with MFS were recruited at Johns Hopkins if they completed a STOP-BANG survey. Composite survey scores were categorised into those with low OSA risk (STOP-BANG ResultsOf the 89 participants studied, 28% had a high OSA risk and 32% had aortic grafts. Persons with high OSA risk had greater aortic root diameter (mm) (ß=4.13, SE=1.81, p=0.027) and aortic root dilatation (ß=2.80, SE=1.34, p=0.046) compared with those with low OSA risk . In addition, the odds of prior aortic root replacement was three times greater in those with high OSA risk compared with those with low OSA risk.ConclusionIn MFS, high OSA risk is associated with aortic enlargement and a threefold increased risk of having had prior aortic root replacement. These findings invite further exploration of the relationship between OSA and aortic disease in MFS, and studies to clarify whether targeted interventions for OSA might mitigate aortic disease progression in MFS.Registration numberIRB00157483.

Objective To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. Study design In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. Results Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time x Genotype interaction P =.005, mean annual z-score change +/- SE -0.20 +/- 0.03 vs -0.09 +/- 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P =.002; -0.20 +/- 0.02 vs -0.07 +/- 0.02; P

Background: Bicuspid aortic valve (BAV) is the most prevalent congenital heart defect affecting 1% to 2% of the population. It is associated with ascending aorta dilatation. Valve morphology, aortic stenosis (AS), and aortic insufficiency (AI) have been proposed as potential risk factors; however, evaluating their role is difficult, as these factors are inherently related. The aim of this study was to determine whether BAV morphology and dysfunction are independent determinants for ascending aorta dilatation in pediatric patients. Methods: A multicenter, retrospective, cross-sectional study of pediatric BAV patients followed since 2004 was performed. Imaging data were assessed for BAV morphology, severity of AS and AI, history of coarctation, and aortic dimensions. Associations were determined using multivariable regression analysis. A subset of patients undergoing aortic interventions (balloon dilation or Ross) were assessed longitudinally. Results: Data were obtained from 2122 patients (68% male; median age 10.2 years). Fifty percent of patients had ascending aorta dilatation. Right and noncoronary cusp fusion, increasing AS and AI, and older age were independently associated with ascending aorta dilatation. A history of coarctation was associated with less ascending aorta dilatation. In patients with neither AS nor AI, 37% had ascending aorta dilatation (4% severe). No complications related to aortic dilatation occurred in this cohort. Aortic Z scores were determined, and a Z -score calculator was created for this population. Conclusions: In this large pediatric cohort of patients with BAV, valve morphology, AS, and AI are independently associated with ascending aorta dilatation, suggesting that hemodynamic factors influence aortopathy. However, even in BAVs with no AS or AI, there is significant ascending aorta dilatation independent of valve morphology. Interventions that led to changes in degree of AI and AS did not seem to influence change in aortic dimensions. The current BAV cohort can be used as a reference group for expected changes in aortic dimensions during childhood.

Loeys–Dietz syndrome (LDS) is a rare autosomal dominant connective tissue disorder, first described in 2005. It is characterized by widespread arterial tortuosity and aneurysmal disease in addition to a variety of skeletal (e.g., pectus excavatum or carinatum, scoliosis, camptodactyly, arachnodactyly), craniofacial (e.g., hypertelorism, bifid uvula, cleft palate, craniosynostosis), and cutaneous (e.g., easy bruising, translucent skin, dystrophic scarring) findings. The diagnosis is based on the presence of clinical findings and/or the identification of a causal variant in one of the known LDS genes. To date, mutations in six genes (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3) have been linked to the disease, all encoding key mediators of the canonical TGFβ signaling pathway. In LDS, dissections tend to occur at younger ages and smaller diameters when compared to other vascular connective tissue disorders. Administration of medications that mitigate biochemical abnormalities and reduce hemodynamic stress, cardiovascular imaging surveillance, and prophylactic surgical intervention represent pivotal management strategies. Malformations, dysfunction, or pain ensuing from the extra-cardiovascular anomalies are dealt with in a case-by-case manner, optimally based on the input of a multidisciplinary team of medical specialists.

A connective tissue disorder is any disease that impacts the structures between cells, typically impacting collagen or elastin protein production or function. Heritable disorders of connective tissue is a broad category, ranging from a description of nonspecific features (hypermobility, flat feet, scoliosis) seen somewhat commonly in the general population to genetic syndromes typically without vascular involvement (Stickler syndrome, Ehlers–Danlos syndrome) to syndromes predisposing to vascular tear or rupture (heritable thoracic aortic disease).

Objectives We sought to develop strategies for management of the aortic arch in patients with Loeys–Dietz syndrome (LDS) through a review of our clinical experience with these patients and a comparison with our experience in patients with Marfan syndrome (MFS). Methods We reviewed hospital and follow-up records of 79 patients with LDS and compared them with 256 patients with MFS who served as reference controls. Results In the LDS group, 16% of patients presented initially with acute aortic dissection (AAD) (67% type A, 33% type B) or developed AAD during follow-up, compared with 10% of patients with MFS (95% type A, 5% type B). There was no difference between patients with LDS or MFS in need for subsequent arch interventions after aortic root surgery (46% vs 50%, P = 1.0). Among the patients who never had AAD, the need for arch repair at initial root surgery was greater in patients with LDS (5% vs 0.4%, P = .04), as was the need for any subsequent aortic surgery (12% vs 1.3%, P = .0004). Late mortality in patients with LDS after arch repair was greater than in those patients who had no arch intervention (33% vs 6%, P = .007). Conclusions In the absence of dissection, patients with LDS have a greater rate of arch intervention after root surgery than patients with MFS. After a dissection, arch reintervention rates are similar in the 2 groups. Arch intervention portends greater late mortality in LDS.

Despite significant research efforts, clinical practice for arterial bypass surgery has been stagnant, and engineered grafts continue to face postimplantation challenges. Here, we describe the development and application of a durable small-diameter vascular graft with tailored regenerative capacity. We fabricated small-diameter vascular grafts by electrospinning fibrin tubes and poly(ε-caprolactone) fibrous sheaths, which improved suture retention strength and enabled long-term survival. Using surface topography in a hollow fibrin microfiber tube, we enable immediate, controlled perfusion and formation of a confluent endothelium within 3–4 days in vitro with human endothelial colony-forming cells, but a stable endothelium is noticeable at 4 weeks in vivo. Implantation of acellular or endothelialized fibrin grafts with an external ultrathin poly(ε-caprolactone) sheath as an interposition graft in the abdominal aorta of a severe combined immunodeficient Beige mouse model supports normal blood flow and vessel patency for 24 weeks. Mechanical properties of the implanted grafts closely approximate the native abdominal aorta properties after just 1 week in vivo. Fibrin mediated cellular remodeling, stable tunica intima and media formation, and abundant matrix deposition with organized collagen layers and wavy elastin lamellae. Endothelialized grafts evidenced controlled healthy remodeling with delayed and reduced macrophage infiltration alongside neo vasa vasorum-like structure formation, reduced calcification, and accelerated tunica media formation. Our studies establish a small-diameter graft that is fabricated in less than 1 week, mediates neotissue formation and incorporation into the native tissue, and matches the native vessel size and mechanical properties, overcoming main challenges in arterial bypass surgery.

BACKGROUND Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events. OBJECTIVES The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework. METHODS We applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening, All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel. RESULTS Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD. CONCLUSIONS The ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease, (C) 2018 the American College of Cardiology Foundation, Published by Elsevier. Alt rights reserved.

Background: Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5-7% of the population and can be reversed by diet. This approach presupposes that hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA.Objective: We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFS mouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA.Methods: Murine fibrillin 1 gene (Fbn1)C1039G/+ MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk.Results: Cobalamin-restricted mice exhibited significantly higher homocysteine (P < 0.0001) and methylmalonic acid (P < 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet.Conclusions:Fbn1C1039G/+ mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.

In pediatric patients with connective tissue disorders (CTDs), early cardiac presentation often involves severe mitral regurgitation (MR) associated with severe bileaflet prolapse and, less frequently, aortic root enlargement. We adopted a simplified repair to address MR and prevent systolic anterior motion (SAM) in this unique group of patients.Retrospective review of clinical and echocardiographic data of all pediatric patients (age 18 years) with CTD and MR undergoing simplified repair at 3 institutions (2000-2014).Eighteen children who underwent surgery for severe MR and bileaflet prolapse were identified. All were treated with ring annuloplasty and Alfieri edge-to-edge repair. Median age and weight were 8.2 years (range, 0.4-17.2 years) and 24.9 kg (5.6-63.3 kg), respectively. Median left ventricular end diastolic dimension median z score was 4.9 (2.1-11.9). One patient died (5.6%), and there were no other major complications. Among survivors, 94.4% had mild regurgitation or less, with no stenosis or SAM at median clinical follow-up of 2.4 years (range, 0-13.9 years). Median left ventricular end-diastolic dimension z score regressed to 1.3 (-0.5 to 4.3).In pediatric patients with CTD and severe MR, a simplified approach is associated with intermediate-term competence, absence of SAM or significant stenosis, and regression of left ventricular enlargement.

Contains fulltext : 175552.pdf (Publisher’s version ) (Open Access) PURPOSE: 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. METHODS: 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. RESULTS: 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-beta 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. CONCLUSION: 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-beta signaling.Genet Med 19 4, 386-395.

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-β-dependent homeostasis of connective tissues.

Fibrosis is a common pathologic outcome of chronic disease resulting in the replacement of normal tissue parenchyma with a collagen-rich extracellular matrix produced by myofibroblasts. Although the progenitor cell types and cellular programs giving rise to myofibroblasts through mesenchymal transition can vary between tissues and diseases, their contribution to fibrosis initiation, maintenance, and progression is thought to be pervasive. Here we showed that the ability of transforming growth factor-β (TGFβ) to efficiently induce myofibroblast differentiation of cultured epithelial cells, endothelial cells, or quiescent fibroblasts is dependent upon the induced expression and activity of dimeric calpains, a family of non-lysosomal cysteine proteases that regulate a variety of cellular events through post-translational modification of diverse substrates. siRNA-based gene silencing demonstrated that TGFβ-induced mesenchymal transition of a murine breast epithelial cell line was dependent upon induction of expression of calpain 9 (CAPN9), an isoform previously thought to be restricted to the gastrointestinal tract. Mice lacking functional CAPN9 due to biallelic targeting of Capn9 were viable and fertile, but showed overt protection from bleomycin-induced lung fibrosis, carbon tetrachloride-induced liver fibrosis, and angiotensin II-induced cardiac fibrosis and dysfunction. A predicted loss-of-function allele of CAPN9 is common in Southeast Asia, with the frequency of homozygosity matching the prediction of Hardy-Weinberg equilibrium; together with the highly spatially-restricted pattern of CAPN9 expression under physiologic circumstances and the heartiness of the murine knockout, these data provide a strong signature for tolerance of therapeutic strategies for fibrosis aimed at CAPN9 antagonism.

In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor-β2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFβ2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.

Vascular Ehlers-Danlos Syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene[1][1]. Currently, loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including

Objective: Bicuspid aortic valve is a common risk factor for thoracic aortic aneurysm and dissection. Guidelines for elective ascending aortic intervention (AAI) in bicuspid aortic valve are derived from limited evidence, and the extent of practice variation due to patient and provider characteristics is unknown. Using data from 2 large cardiovascular registries, we investigated factors that influence decisions for AAI. Methods: All bicuspid aortic valve cases with known aortic diameters and surgical status were included. We used multivariable logistic regression to profile predictors of isolated aortic valve replacement (AVR) or AVR+AAI, stratified by patient characteristics, surgical indications, and institution. Results: We studied 2861 subjects at 18 institutions from 1996 to 2015. The median aortic diameter of patients who underwent AVR+AAI varied widely across institutions (39-52 mm). Aortic diameters were

Background: In patients with ascending aortic aneurysms (AscAA), biomechanical differences are seen among patients with congenital bicuspid aortic valves (BAV), Marfan syndrome (MFS), and tricuspid aortic valves (TAV). We examined the hemodynamic profiles and ultrastructures of aneurysmal specimens, focusing on vascular remodelling to better understand AscAA pathogenesis. Methods: A total of 795 patients with BAV (43.97 +/- 0.51 years; 93.2% male), 69 with MFS (34.43 +/- 1.44 years; 86.2% male), and 90 with TAV (67.27 +/- 0.58 years; 60% male) were enrolled, primarily upon admission with AscAA. The biomechanical properties of the aortic root were assessed and intraoperative specimens were analyzed by light-microscopy and two-photon autofluorescence microscopy. Results: Patientswith BAV had significantly greater distension of the aortic root, irrespective of age or aneurysmal widening (R-2= 0.543, p < 0.05). This was associated with significantly increase in the size of the tunica media. Patients with MFS displayed significant stiffness in the sinuses that worsened with age (R-2 = 0.752, p < 0.001), similar to patients with TAV (R-2= 0.626, p < 0.05). Patients with MFS showed significant root elasticity with aneurysmal growth (R-2 = 0.596, p < 0.05) and increased medial degeneration. Patients with TAV maintained biomechanical properties, apart from aneurysmal dimensions and high levels of inflammation. Conclusions: Among patientswith AscAA, those with BAVmaintain tissue elasticity in the aortic root, regardless of age. Patients with MFS demonstrate increased sinus stiffness with medial degeneration, both during aging and with aneurysmal growth. Patients with TAV and AscAA present with increased inflammation. (c) 2018 Published by Elsevier B.V.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%) that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype. Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%) that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.

Background Aortic dissection (AoD) is a serious complication of thoracic aortic aneurysm (TAA). Relative risk for AoD in relation to TAA etiology, incidence, and pattern after prophylactic TAA surgery are poorly understood. Objectives This study sought to determine the incidence, pattern, and relative risk for AoD among patients with genetically associated TAA. Methods The population included adult GenTAC participants without AoD at baseline. Standardized core laboratory tests classified TAA etiology and measured aortic size. Follow-up was performed for AoD. Results Bicuspid aortic valve (BAV) (39%) and Marfan syndrome (MFS) (22%) were the leading diagnoses in the studied GenTAC participants (n = 1,991). AoD occurred in 1.6% over 3.6 ± 2.0 years; 61% of AoD occurred in patients with MFS. Cumulative AoD incidence was 6-fold higher among patients with MFS (4.5%) versus others (0.7%; p Conclusions Among patients with genetically associated TAA, MFS augments risk for AoD even after TAA grafting. Although increased aortic size is a risk factor for subsequent AoD, events typically occur below established thresholds for prophylactic TAA repair.

Prophylactic aortic root replacement improves survival in patients with Marfan syndrome with aortic root aneurysms, but the optimal procedure remains undefined.Adult patients with Marfan syndrome who had Bentall or aortic valve-sparing root replacement (VSRR) procedures between 1997 and 2013 were identified. Comprehensive follow-up information was obtained from hospital charts and telephone contact.One hundred sixty-five adult patients with Marfan syndrome (aged20 years) had either VSRR (n = 98; 69 reimplantation, 29 remodeling) or Bentall (n = 67) procedures. Patients undergoing Bentall procedure were older (median, 37 vs 36 years; P = .03), had larger median preoperative sinus diameter (5.5 cm vs 5.0 cm; P = .003), more aortic dissections (25.4% vs 4.1%; P.001), higher incidence of moderate or severe aortic insufficiency (49.3% vs 14.4%; P.001) and more urgent or emergent operations (24.6% vs 3.3%; P.001). There were no hospital deaths and 9 late deaths in more than 17 years of follow-up (median, 7.8 deaths). Ten-year survival was 90.5% in patients undergoing Bentall procedure and 96.3% in patients undergoing VSRR (P = .10). Multivariable analysis revealed that VSRR was associated with fewer thromboembolic or hemorrhagic events (hazard ratio, 0.16; 95% confidence interval, 0.03-0.85; P = .03). There was no independent difference in long-term survival, freedom from reoperation, or freedom from endocarditis between the 2 procedures.After prophylactic root replacement in patients with Marfan syndrome, patients undergoing Bentall and valve-sparing procedures have similar late survival, freedom from root reoperation, and freedom from endocarditis. However, valve-sparing procedures result in significantly fewer thromboembolic and hemorrhagic events.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that has phenotypic overlap with Marfan syndrome. In LDS, the aortic root dissections can be more aggressive and occur at a younger age than Marfan syndrome.Review of two cases.A 7-year old boy with history of LDS was found to have a vitreous hemorrhage in the right eye. Further examination showed findings of Familial Exudative Vitreoretinopathy (FEVR). Both eyes were found to have peripheral non-perfusion and neovascularization. A non-related 25-month-old boy with no molecularly confirmed connective tissue disorder was found to have bilateral peripheral non-perfusion and bilateral tractional retinal detachments. The boy was clinically diagnosed with Larsen syndrome, Ehlers-Danlos syndrome kyphoscoliotic form, and Marfan syndrome before presentation. The FEVR lead to consideration of LDS that was molecularly confirmed. Consequently, he was monitored for aortic root dilation.FEVR findings may lead to diagnosis of LDS and patients with LDS may present with proliferative retinopathy.

Objectives We sought to characterize pregnancy-related aortic complications in women with Marfan's syndrome who had prior aortic root replacement. Study Design This is a retrospective case series study and literature review of women with Marfan's syndrome with pregnancy after aortic root replacement. We surveyed women with Marfan's syndrome who had successful pregnancy after aortic root replacement using the Marfan Foundation Website and from two large tertiary care Marfan's clinics. Clinical data, counseling information, and details of pregnancy-related aortic complications were compiled. A literature review was performed assessing aortic outcomes in women with Marfan's syndrome with pregnancy after aortic surgery. Results Fourteen women with 20 pregnancies were identified. Two women had three pregnancies following root replacement for aortic dissection. There were no aortic dissections during the 20 pregnancies. In contrast, aortic dissection was frequently reported in the literature. Conclusions Women with Marfan's syndrome who become pregnant following aortic root replacement remain at risk for distal aortic dissection related to pregnancy. The exact risk is difficult to quantify but is not zero and women should be counseled accordingly.

Background: Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability. Case presentation: We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (pArg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far. Conclusions: This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.

The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1C1041G/+) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-β-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingenuity Pathway Analysis of over 1,000 proteins quantified from the in vivo MFS mouse aorta by data-independent acquisition mass spectrometry revealed a predicted upstream regulator, Rictor, that was selectively activated in aged MFS mice. We validated this pattern of Rictor activation in vivo by Western blot analysis for phosphorylation on Thr1135 in a separate cohort of mice and showed in vitro that TGF-β activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of β3-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that β3-integrin expression and activation modulated TGF-β-induced Rictor phosphorylation in vitro, and this signaling effect was associated with an altered vascular smooth muscle cell proliferative-migratory and metabolic in vitro phenotype that parallels the in vivo aneurysm phenotype in MFS. These results reveal that Rictor is a novel, context-dependent, noncanonical TGF-β signaling effector with potential pathogenic implications in aortic aneurysm. NEW & NOTEWORTHY We present the most comprehensive quantitative analysis of the ascending aortic aneurysm proteome in Marfan syndrome to date resulting in novel and potentially wide-reaching findings that expression and signaling by β3-integrin constitute a modulator of transforming growth factor-β-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells.

OBJECTIVE This study aimed to determine if carotid arterial tortuosity represents a marker of disease severity in Loeys-Dietz syndrome (LDS). METHODS Fifty-four 54 LDS patients (mean age, 17.0 years) who underwent computed tomogram angiography from January 2004 to December 2013 were retrospectively identified. Carotid artery tortuosity index (CATI) was calculated from computed tomogram angiography. Clinical variables were obtained from the medical records. Relationship between CATI and need for aortic root replacement was evaluated with Cox proportional hazard model and Kaplan-Meier analysis. RESULTS Higher CATI was associated with the need for aortic root replacement (P < 0.001) in the univariate Cox proportional hazard model. Patients were stratified based on both CATI and aortic root size in Kaplan-Meier analysis, and patients with higher CATI were more likely to require aortic root replacement (P < 0.001) in both aortic root size strata. CONCLUSION Increased carotid artery tortuosity is associated with the need for early aortic root replacement in patients with LDS.

Background We studied the prevalence and treatment outcomes of spondylolisthesis in patients with Loeys-Dietz syndrome (LDS). Methods Clinical data and lumbosacral imaging of 138 patients with LDS were reviewed. Spondylolisthesis (L4-L5 or L5-S1) and spondylolysis were characterized by multimodal imaging and correlated with clinical data. Treatments and outcomes were characterized for patients with spondylolisthesis. Associations were determined using the Fisher exact, Mann-Whitney, and Student t tests (α=0.05). Results Twenty-four patients (17%) had spondylolysis and 23 (17%) had spondylolisthesis. Median age at spondylolisthesis diagnosis was 11 (interquartile range, 9.5) years. In patients in whom measurement was possible (n=20), mean (±SD) slip was 48% (±35%). Nineteen patients had L5-S1 slip and 4 had L4-L5 slip. Of the patients with spondylolisthesis, 5 had no evidence of spondylolysis; of those with spondylolysis, all but 6 had spondylolisthesis. Eleven patients with spondylolisthesis underwent posterior spinal fusion (PSF) to treat slip progression, pain, and/or neurological deficit. Spondylolisthesis recurred in 1 patient who underwent PSF with bone graft arthrodesis alone (no instrumentation). The other 10 patients underwent PSF with instrumentation and fusion. Three patients additionally underwent Bohlman interbody fusion. Two patients developed implant failure. S2 fixation was performed at revision to achieve fusion in these patients. Mean Meyerding grade improved in patients who underwent arthrodesis, from 3.9 (±1.2) to 1.9 (±1.3) (P=0.002). Complications were 2 cerebrospinal fluid leaks, 2 transient postoperative paresthesias, and 1 case each of pseudarthrosis at S1-S2, wound dehiscence, and transient urinary incontinence. No significant associations between LDS type and lumbosacral abnormalities were found. Conclusions High-grade spondylolisthesis is common in LDS and usually associated with spondylolysis. Patients requiring surgery for spondylolisthesis present during childhood and do well after instrumented PSF. Interbody fusion and stabilization of S1 and S2 can prevent physeal deformation. LDS should be considered in patients with high-grade spondylolisthesis. Patients with LDS should be monitored for spondylolisthesis and spondylolysis starting when they are young. Level of evidence Level IV-retrospective study.

Objective Valve-sparing root replacement is an attractive alternative to composite mechanical or biologic prostheses for aortic root aneurysms in children. Data on outcomes in pediatric patients are limited. We present our institutional experience with 100 consecutive pediatric valve-sparing aortic root procedures. Methods All children who underwent valve-sparing root replacement at our institution from May 1997 to August 2017 were identified, and echocardiographic and clinical data were reviewed. The primary end point was mortality, and secondary end points included complications, further interventions, and subsequent valvular dysfunction. Results Median age at operation was 13.6 years (interquartile range, 9.42-15.9); 51 patients (51%) had Marfan syndrome, and 39 patients (39%) had Loeys–Dietz syndrome. Mean preoperative maximum sinus diameter was 4.4 ± 0.71 cm (z score 7.3 [5.7-9.3]). Most patients (n = 80, 80%) underwent reimplantation procedures with a Valsalva graft. Four patients (4%) underwent David I reimplantation with a straight-tube graft, 13 patients (13%) underwent a Yacoub remodeling procedure, and 3 patients (3%) underwent a Florida sleeve procedure. Perioperative valve-sparing root replacement mortality was 2% (n = 2). Six patients required late reintervention for development of pseudoaneurysms. Eight patients underwent additional aortic surgery. Average time to reoperation was 7.23 ± 4.56 years. Of the 84 patients undergoing a reimplantation procedure, 5 (5.9%) underwent late valve replacement versus 5 (33.3%) of the 15 patients who received a remodeling procedure (P = .001). Conclusions Valve-sparing root replacement is a safe and effective option for children with aortic root aneurysms in children. The reimplantation procedure is preferred. Late aortic insufficiency and pseudoaneurysm formation remain late concerns.

Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak at term, are sustained after delivery, and might synergize with previously defined signaling pathways implicated in aneurysm progression, we examined the hormone oxytocin, which initiates uterine contraction and milk letdown for the duration of lactation through phosphorylation of extracellular signal-regulated kinase (ERK). In a mouse model of MFS that shows highly penetrant postnatal aortic dissection, risk was strongly attenuated by preventing lactation or use of an oxytocin receptor antagonist. Survival correlated inversely with the extent of ERK activation in the aortic wall, and strong protection was observed upon attenuation of ERK phosphorylation using an inhibitor of ERK kinase (MEK) or the U.S. Food and Drug Administration-approved medication hydralazine, offering potential therapeutic strategies for pregnancy-associated vascular catastrophe in the setting of MFS.

PurposeWe delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.MethodsWe retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.ResultsStenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.ConclusionOur findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.GENETICS in MEDICINE advance online publication, 11 January 2018; doi:10.1038/gim.2017.253. ispartof: Genetics in Medicine vol:20 issue:10 pages:1236-1245 ispartof: location:United States status: published

Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular and skeletal abnormalities resembling Marfan syndrome, including a predisposition for pathologic fracture. LDS is caused by heterozygous mutations in the genes encoding transforming growth factor-β (TGF-β) type 1 and type 2 receptors. In this study, we characterized the skeletal phenotype of mice carrying a mutation in the TGF-β type 2 receptor associated with severe LDS in humans. Cortical bone in LDS mice showed significantly reduced tissue area, bone area, and cortical thickness with increased eccentricity. However, no significant differences in trabecular bone volume were observed. Dynamic histomorphometry performed in calcein-labeled mice showed decreased mineral apposition rates in cortical and trabecular bone with normal numbers of osteoblasts and osteoclasts. Mechanical testing of femurs by three-point bending revealed reduced femoral strength and fracture resistance. In vitro, osteoblasts from LDS mice demonstrated increased mineralization with enhanced expression of osteoblast differentiation markers compared with control cells. These changes were associated with impaired TGF-β1-induced Smad2 and Erk1/2 phosphorylation and upregulated TGF-β1 ligand mRNA expression, compatible with G357W as a loss-of-function mutation in the TGF-β type 2 receptor. Paradoxically, phosphorylated Smad2/3 in cortical osteocytes measured by immunohistochemistry was increased relative to controls, possibly suggesting the cross-activation of TGF-β-related receptors. The skeletal phenotype observed in the LDS mouse closely resembles the principal structural features of bone in humans with LDS and establishes this mouse as a valid in vivo model for further investigation of TGF-β receptor signaling in bone.

Item does not contain fulltext At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To circumvent these problems, we developed a TAA gene panel for next-generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation-dependent probe amplification identified large deletions in six of the remaining samples, whereas false-negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes.

A recent emphasis on individualized medicine reflects a desire to transition currently prevailing evidence-based practices (What works best for the average patient?) to more informed and tailored approaches (What will work best for this patient or subgroup?). It has been both expected and realized that genotypic information will contribute prominently to this endeavor. In this issue of Circulation Cardiovascular Genetics , Franken et al1 report that the angiotensin receptor blocker (ARB) losartan is particularly effective at suppressing aortic root aneurysm progression in patients with Marfan syndrome (MFS) that are heterozygous for mutations in the fibrillin-1 gene ( FBN1 ) that create a premature termination codon, when compared with other mutation classes expected to express abnormal protein from the mutant allele. Given the intuitive importance of this finding, it is worth exploring its potential biological foundations, while also considering alternative explanations. Article see p 383 MFS is an autosomal-dominant systemic disorder of connective tissue with prominent involvement of the ocular, skeletal, and cardiovascular systems, including a strong predisposition for eye lens dislocation (ectopia lentis) and myopia, long-bone overgrowth and other skeletal deformity, and progressive aortic root dilatation and tear (dissection), respectively. The condition is caused by heterozygous mutations in FBN1 that encodes the extracellular matrix protein fibrillin-1. Fibrillin-1 monomers aggregate to form complex extracellular structures called microfibrils and an extracellular deficiency of microfibrils is thought to be the sentinel event in MFS pathogenesis. Missense mutations are the most common type causing MFS, with particularly high frequency of substitutions that either destroy or create cysteine residues in repetitive epidermal growth factor–like or latent transforming growth factor-β (TGF-β)–binding protein–like domains that each have 6 or 8 obligate cysteines with predictable spacing, respectively, that are required for proper intradomain folding. The FBN1 mutational repertoire also includes all other types of mutations, including insertions/deletions (indels) or …

Background: Loeys-Dietz syndrome is a connective tissue disorder characterized by vascular, craniofacial, and musculoskeletal malformation. Our goal was to report the manifestations, surgical treatment, and complications in the cervical spine in patients with Loeys-Dietz syndrome. Methods: We reviewed the clinical and cervical spine imaging data of eighty patients with Loeys-Dietz syndrome who were seen at our institution from January 2005 through January 2014. Their mean age at presentation was 17.3 years (range, three months to seventy-five years). We tested associations with use of the Fisher exact test (type of TGF-βR [transforming growth factor-beta receptor] mutation and cervical abnormalities) and the Student t test (age at presentation and type of TGF-βR mutation) (significance, p = 0.05). Results: Vertebral anomalies and cervical instability were common; we found no significant association of TGF-βR-type with cervical abnormalities or age at presentation. Twenty-eight patients had atlas defects (anterior and/or posterior arch defects or hypoplasia), fifty-three had axis malformations (elongation, apex-anterior dens angulation, or spondylolysis), and twelve had focal kyphosis. Ten patients had hypoplastic subaxial vertebrae, leading to focal kyphosis (eight) and subaxial instability (nine). Eight patients had atlantoaxial instability. Of the thirteen patients with cervical instability, nine were treated surgically: fusion (eight patients) and halo application (one) (mean age, four years; range, three months to twelve years). Postoperative complications (seven patients) were pseudarthrosis, failure of fixation, junctional kyphosis or instability, and development of occipital-cervical instability. Conclusions: Cervical midline defects (most often C1-C3) are common in Loeys-Dietz syndrome. Patients have a high prevalence of cervical instability, particularly a pattern of instability at C2-C3 associated with C3 vertebral body hypoplasia and C2-C3 focal kyphosis. Patients requiring surgery typically present in early childhood. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The transforming growth factor β (TGF-β) family of signaling molecules, which includes TGF-βs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-β family members play different roles in these tissues, and their activities are often balanced with those of other TGF-β family members and by interactions with other signaling pathways. Perturbations in TGF-β family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-β family of signaling mediators and the extracellular matrix in connective tissues.

textabstractIn the original article, we noted two mutation annotation errors. The correction of these two mistakes does not change the scientific conclusions in any way. The authors apologize for these nomenclature errors. Please find below the corrected annotations of those two mutations: (1) The correct RNA and protein annotations of the SMAD6 variant in P99 are c.455_461del and p.Pro152Profs*27, and not c.454_461del and p.Gly166Valfs*23. (2) The correct RNA and protein annotations of the SMAD6 variant in P128 are c.74_79del and p.Ser27_Gly28del, and not c.73_79del and p.Gly26_Ser27del. As a consequence, a correction has been made to RESULTS, Paragraphs 5 and 6: The SMAD6 c.726del variant leads to a frameshift (p.Lys242Asnfs*300) and a predicted protein with a C-terminal extension due to loss of the intended stop codon. The c.455_461del frameshift variant (p.Pro152Profs*27) causes the introduction of a premature stop codon, most likely resulting in haploinsufficiency due to nonsense-mediated mRNA decay (NMD). Also the two nonsense variants (p.Tyr279* and p.Tyr288*) are predicted to lead to NMD. All of the missense variants cluster in the functionally important MH1 and MH2 domains (Makkar et al., 2009) (amino acids 148-275 and 331-496, respectively), which is not the case for the sole missense variant (p.Ser130Leu) found in a control individual (Figure 2). All but one (p.Arg443His) of the identified variants were absent in the ExAC control cohort (v0.3.1; Supplementary Table 2). Moreover, the missense variants in the patient cohort (7/7) are enriched in the MH1 and MH2 domains when compared to ExAC controls (n = 228/430; p = 0.02).

Biallelic mutations in ABCC6 cause pseudoxanthoma elasticum (PXE), a disease characterized by calcification in the skin, eyes, and blood vessels. The function of ATP-binding cassette C6 (ABCC6) and the pathogenesis of PXE remain unclear. We used mouse models and patient fibroblasts to demonstrate genetic interaction and shared biochemical and cellular mechanisms underlying ectopic calcification in PXE and related disorders caused by defined perturbations in extracellular adenosine 5′-triphosphate catabolism. Under osteogenic culture conditions, ABCC6 mutant cells calcified, suggesting a provoked cell-autonomous defect. Using a conditional Abcc6 knockout mouse model, we excluded the prevailing pathogenic hypothesis that singularly invokes failure of hepatic secretion of an endocrine inhibitor of calcification. Instead, deficiency of Abcc6 in both local and distant cells was necessary to achieve the early onset and penetrant ectopic calcification observed upon constitutive gene targeting. ABCC6 mutant cells additionally had increased expression and activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme that degrades pyrophosphate, a major inhibitor of calcification. A selective and orally bioavailable TNAP inhibitor prevented calcification in ABCC6 mutant cells in vitro and attenuated both the development and progression of calcification in Abcc6 −/− mice in vivo, without the deleterious effects on bone associated with other proposed treatment strategies.

Contains fulltext : 176973.pdf (Publisher’s version ) (Open Access) Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter >/= 4.0 cm in adults, or a Z-score >/= 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype.

OBJECTIVE. Arterial dissection and aneurysm rupture are significant sources of morbidity and mortality in patients with connective tissue diseases. This article provides a detailed analysis of cardiovascular involvement in Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome. CONCLUSION. Although these syndromes share some overlapping features, they have discriminating clinical and imaging features, and knowledge of these features enables the radiologist to aid the referring clinician in making the correct diagnosis.

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. Hutchinson-Gilford Progeria Syndrome (HGPS) is characterized by the clinical features of accelerated aging in childhood. Both MAD and HGPS can be caused by mutations in theLMNAgene. In this study, we describe a 2-year-old boy with overlapping features of MAD and HGPS. Mutation analysis of theLMNAgene revealed a homozygous missense change, p.M540T, while only the mother carries the mutation. Uniparental disomy (UPD) analysis for chromosome 1 showed the presence of maternal UPD. Markers in the 1q21.3–q22 region flanking theLMNAlocus were isodisomic, while markers in the short arm and distal 1q region were heterodisomic. These results suggest that nondisjunction in maternal meiosis followed by loss of the paternal chromosome 1 during trisomy rescue might result in the UPD1 and homozygosity for the p.M540T mutation observed in this patient.