Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype.

MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. We report four patients from three families presenting with a MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants. However, it revealed likely pathogenic missense variants in three individuals [c.3936G > T p.(Lys1312Asn), c.193G > A p.(Asp65Asn)] and a missense variant of unknown significance in the fourth patient [c.4013G > A p.(Ser1338Asn)] in propeptide coding regions of COL2A1. Pathogenic COL2A1 variants are associated with type II collagenopathies comprising a remarkable clinical variablility. Main features include skeletal dysplasia, ocular anomalies, and auditory defects. A MASS-like phenotype has not been associated with COL2A1 variants before. Thus, the identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. We compare the phenotypes of our patients with related disorders of connective tissue and discuss possible pathomechanisms and genotype-phenotype correlations for the identified COL2A1 variants. Our data recommend COL2A1 sequencing in FBN1-negative patients suggestive for MASS/Marfan-like phenotype (without aortopathy).

Diagnostic accuracy study of routine echocardiography for bicuspid aortic valve: a retrospective study and meta-analysis.

BACKGROUND: Transthoracic echocardiography (TTE) is the standard procedure to distinguish tricuspid aortic valve (TAV) from bicuspid aortic valve (BAV). Published studies assessed the accuracy of TTE for BAV under ideal conditions. Conversely, we aimed at assessing accuracy of TTE for BAV under routine conditions. METHODS: This retrospective, cross-sectional study of 216 adults included 132 men aged 62±14 years. Of these, 108 had BAV and 108 were age-matched individuals with TAV. All diagnoses were confirmed at surgery. We assessed TTE in two patient groups. First, in the (I) group of all 216 individuals, where we assessed accuracy for BAV according to the original diagnoses as documented by the primary investigators during original TTE examination. Second, we assessed accuracy for BAV according to expert re-evaluation in (II) all 158 TTE with availability of original recordings. Third, we performed a meta-analysis of published results on the accuracy of TTE for BAV according to PRISMA standards. RESULTS: Sensitivity, specificity and accuracy of (I) primary investigators was 46.3%, 97.2, and 71.8% as compared to (II) expert re-evaluation with 59.7%, 93%, and 77.8%, respectively. Sensitivity was significantly higher at re-evaluation (P<0.001). TTE at a non-tertiary care center (P=0.012), presence of aortic aneurysm (P=0.001) and presence of severe aortic valve calcification (P=0.003) predicted an inaccurate diagnosis of BAV. Conversely, meta-analysis of published TTE studies identified a pooled sensitivity of 87.7% and a pooled specificity of 88.3% for BAV. CONCLUSIONS: The current study shows that TTE yields almost ideal diagnostic accuracy when ideal investigators examine ideal patients. However, the study also shows that TTE yields suboptimal diagnostic accuracy under routine conditions. TTE in non-tertiary care settings, concomitant aortic aneurysm, and presence of severe aortic valve calcification predict an inaccurate diagnosis of BAV.

Economic and care considerations of Marfan syndrome.

INTRODUCTION: Marfan syndrome is a rare multisystem disease of the connective tissue, which affects multiple organ systems. advances in healthcare have doubled the life-expectancy of patients over the past three decades. to date, there is no comprehensive review that consolidates economic considerations and care for marfan patients. Areas covered: Present research suggests that there may be a link between treatment pattern, disease progression and economic costs of Marfan syndrome. It indicates that an early detection of the disease and preventive interventions achieve a dual aim. From a patient perspective, it may reduce the amount of emergency surgery or intervention, and inpatient stays. In addition, it slows disease progression, lowers lifestyle restrictions, reduces psychological stress, and improves health-related quality of life. Expert commentary: Early detection and preventive measures are likely to achieve a dual aim by simultaneously containing costs and reducing the number and length of inpatient stays.

Mitral valve prolapse syndrome and MASS phenotype: Stability of aortic dilatation but progression of mitral valve prolapse.

BACKGROUND: Mitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS. METHODS: This retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38 ± 17 years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42 ± 15 years with mean follow-up of 66 ± 49 months. RESULTS: At baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all P < .001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P < .001). In contrast, the incidence of endocarditis (P = .292), heart failure (P = .644), and mitral valve surgery (P = .140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P = .013), moderate MVR (P = .019) and flail MV leaflet (P = .017) as independent predictors of mitral valve surgery. CONCLUSIONS: The study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse.

The main pulmonary artery in adults: a controlled multicenter study with assessment of echocardiographic reference values, and the frequency of dilatation and aneurysm in Marfan syndrome.

BACKGROUND: Echocardiographic upper normal limits of both main pulmonary artery (MPA) diameters (MPA-d) and ratio of MPA to aortic root diameter (MPA-r) are not defined in healthy adults. Accordingly, frequency of MPA dilatation based on echocardiography remains to be assessed in adults with Marfan syndrome (MFS). METHODS: We enrolled 123 normal adults (72 men, 52 women aged 42 ± 14 years) and 98 patients with MFS (42 men, 56 women aged 39 ± 14 years) in a retrospective cross-sectional observational controlled study in four tertiary care centers. We defined outcome measures including upper normal limits of MPA-d and MPA-r as 95 quantile of normal persons, MPA dilatation as diameters > upper normal limits, MPA aneurysm as diameters >4 cm, and indication for surgery as MPA diameters >6 cm. RESULTS: MPA diameters revealed normal distribution without correlation to age, sex, body weight, body height, body mass index and body surface area. The upper normal limit was 2.6 cm (95% confidence interval (CI) =2.44-2.76 cm) for MPA-d, and 1.05 (95% CI = .86-1.24) for MPA-r. MPA dilatation presented in 6 normal persons (4.9%) and in 68 MFS patients (69.4%; P < .001), MPA aneurysm presented only in MFS (15 patients; 15.3%; P < .001), and no patient required surgery. Mean MPA-r were increased in MFS (P < .001), but ratios >1.05 were equally frequent in 7 normal persons (5%) and in 8 MFS patients (10.5%; P = .161). MPA-r related to aortic root diameters (P = .042), reduced left ventricular ejection fraction (P = .006), and increased pulmonary artery systolic pressures (P = .040). No clinical manifestations of MFS and no FBN1 mutation characteristics related to MPA diameters. CONCLUSIONS: We established 2.6 cm for MPA-d and 1.05 for MPA-r as upper normal limits. MFS exhibits a high prevalence of MPA dilatation and aneurysm. However, patients may require MPA surgery only in scarce circumstances, most likely because formation of marked MPA aneurysm may require LV dysfunction and increased PASP.