Objective To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome (MFS) participating in the Pediatric Heart Network Marfan Trial. Study design The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with MFS (5–25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol versus losartan), severity of clinical features, and number of patient-reported symptoms (PRS) on HRQOL was assessed by general linear models. Results Mean PedsQL scores in children (5–18 years) with MFS were lower than healthy population norms for physical (P ≤ .003) and psychosocial (P<0.001) domains; mean psychosocial scores for adults (19–25 years) were higher than healthy norms (P<0.001). HRQOL across multiple domains correlated inversely with frequency of PRS (r=0.30–0.38, P<0.0001). Those <18 years of age with neurodevelopmental disorders (ND, mainly learning disability, attention deficit disorder and/or hyperactivity) had lower mean PedsQL scores (5.5–7.4 lower, P<0.04). A multivariable model found age, sex, PRS, and ND to be independent predictors of HRQOL. There were no differences in HRQOL scores by treatment arm, aortic root z-score, number of skeletal features, or presence of ectopia lentis. Conclusions Children and adolescents with MFS were at high risk for impaired HRQOL. PRS and ND, but not treatment arm or severity of MFS-related physical findings, were associated with lower HRQOL.

Losartan on top of beta-blocker therapy has no additional effect on aortic growth or on cardiac function in patients with MFS. Our results are underpowered but are in line with the result from other groups. In order to have a better insight on whether a group of patients could benefit more from losartan therapy, the outcome of an on-going meta-analysis should be awaited.

BackgroundBreast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals.MethodsWe defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established.ResultsWe found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene.ConclusionsWe show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0709-1) contains supplementary material, which is available to authorized users.

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Breast cancer risk drastically increases in individuals with a heterozygous germline BRCA1 or BRCA2 mutation, while it is estimated to equal the population risk for relatives without the familial mutation (non-carriers). The aim of the present study was to use a G2 phase-specific micronucleus assay to investigate whether lymphocytes of healthy BRCA2 mutation carriers are characterized by increased radiosensitivity compared to controls without a family history of breast/ovarian cancer and how this relates to healthy non-carrier relatives. BRCA2 is active in homologous recombination, a DNA damage repair pathway, specifically active in the late S/G2 phase of the cell cycle. We found a significantly increased radiosensitivity in a cohort of healthy BRCA2 mutation carriers compared to individuals without a familial history of breast cancer (P=0.046; Mann-Whitney U test). At the individual level, 50% of healthy BRCA2 mutation carriers showed a radiosensitive phenotype (radiosensitivity score of 1 or 2), whereas 83% of the controls showed no radiosensitivity (P=0.038; one-tailed Fishers exact test). An odds ratio of 5 (95% CI, 1.07–23.47) indicated an association between the BRCA2 mutation and radiosensitivity in healthy mutation carriers. These results indicate the need for the gentle use of ionizing radiation for either diagnostic or therapeutic use in BRCA2 mutation carriers. We detected no increased radiosensitivity in the non-carrier relatives.