Phenotypic spectrum of TGFB3 disease-causing variants in a Dutch-French cohort and first report of a homozygous patient.

Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.

Outcome of adults with Eisenmenger syndrome treated with drugs specific to pulmonary arterial hypertension: A French multicentre study.

BACKGROUND: The relationship between pulmonary arterial hypertension-specific drug therapy (PAH-SDT) and mortality in Eisenmenger syndrome (ES) is controversial. AIMS: To investigate outcomes in patients with ES, and their relationship with PAH-SDT. METHODS: Retrospective, observational, nationwide, multicentre cohort study. RESULTS: We included 340 patients with ES: genetic syndrome (n=119; 35.3%); pretricuspid defect (n=75; 22.1%). Overall, 276 (81.2%) patients received PAH-SDT: monotherapy (endothelin receptor antagonist [ERA] or phosphodiesterase 5 inhibitor [PDE5I]) 46.7%; dual therapy (ERA+PDE5I) 40.9%; triple therapy (ERA+PDE5I+prostanoid) 9.1%. Median PAH-SDT duration was 5.5 years [3.0-9.1 years]. Events (death, lung or heart-lung transplantation) occurred in 95 (27.9%) patients at a median age of 40.5 years [29.4-47.6]. The cumulative occurrence of events was 16.7% [95% confidence interval 12.8-21.6%] and 46.4% [95% confidence interval 38.2-55.4%] at age 40 and 60 years, respectively. With age at evaluation or time since PAH diagnosis as time scales, cumulative occurrence of events was lower in patients taking one or two PAH-SDTs (P=0.0001 and P=0.004, respectively), with the largest differences in the post-tricuspid defect subgroup (P<0.001 and P<0.02, respectively) versus patients without PAH-SDT. By multivariable Cox analysis, with time since PAH diagnosis as time scale, New York Heart Association/World Health Organization functional class III/IV, lower peripheral arterial oxygen saturation and pretricuspid defect were associated with a higher risk of events (P=0.002, P=0.01 and P=0.04, respectively), and one or two PAH-SDTs with a lower risk of events (P=0.009). CONCLUSIONS: Outcomes are poor in ES, but seem better with PAH-SDT. ES with pretricuspid defects has worse outcomes despite the delayed disease onset.

Stenting in paediatric and adult congenital heart diseases: A French multicentre study in the current era.

BACKGROUND: Many stents are used "off-label" during the management of congenital heart diseases (CHD). AIMS: To describe indications for, results of, and adverse events associated with stenting in CHD in current practice. METHODS: Participation in this study was proposed to all catheterization laboratories that specialize in CHD in France (M3C network). All paediatric and adult CHD cases with stent implantation in 2013 were included retrospectively. RESULTS: Overall, 207 stents were implanted in 151 patients across 11 centres. Median age was 13.7 years (range, 5 days to 70.1 years). Main procedure indications were branch pulmonary artery angioplasty (n=46, 29.1%), aortic (re)coarctation stenting (n=43, 27.2%), percutaneous pulmonary valve implantation (n=32, 20.2%) and ductus arteriosus stenting (n=14, 8.9%). The main stents implanted were the CP Stent™ (n=61, 29.5%), the Max™ LD stent (n=43, 20.8%), the Valeo(®) stent (n=28, 13.5%) and valved stents (n=30, 14.5%). Procedures were considered successful in 96.8% of cases (95% confidence interval [CI] 92.8-99.0%). Adverse events were observed in 23 procedures (14.7%, 95% CI 9.5-21.0%). Ductus arteriosus stenting (odds ratio 12.4, 95% CI 2.0-77.5; P<0.01) and pulmonary revalvulation (odds ratio 5.9, 95% CI 1.1-32.3; P=0.04) were risk markers for stent-related adverse events. CONCLUSIONS: Stents are used in various CHD catheterization procedures, from infancy to adult age. The adverse events rate is significant and is related to the type of procedure.