Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex

Flood variability over1871-2012 in Northern Québec: comparison of hydrological reconstructionsbased on tree-rings and on geopotential height field reanalysis

International audienc

Flood variability over 1871-2012 in Northern Québec: comparison of hydrological reconstructions based on tree-rings and on geopotential height field reanalysis

International audienc

Incidence and characteristics of COVID-19 in French professional football players during the 2020-2021 season

International audienceOBJECTIVES: To describe the epidemiology of COVID-19 in French professional football players, and to compare the infection incidence with the general population across the first three waves. METHODS: During the 2020-2021 season, all professional football players (n = 1217) in the two primary French leagues underwent weekly testing for SARS-CoV-2 infection by nasopharyngeal PCR, in combination with rigorous infection control measures. RESULTS: Among all players, 572 (47%) tested positive at least once, with no COVID-19-related death or hospital admission. Monthly incidence estimates in players ranged from 1486 to 6731 per 100,000 individuals, i.e. 2-17 times higher than incidence estimates in the general population in France during the study period. CONCLUSION: Almost 50% of professional football players developed SARS-CoV-2 infection during the 2020-2021 season in France, with no severe complication

Atmospheric analogues for physically consistent scenarios of surface weather in Europe and Maghreb

International audienceFlash-floods are among the most devastating hazards in the Mediterranean. A major subset of damage and casualties caused by flooding is related to road submersion. Distributed hydrological nowcasting can be used for road flooding monitoring. This requires rainfall–runoff simulations at a high space and time resolution.Distributed hydrological models, such as the ISBA-TOP coupled system used in this study, are designed to simulate discharges for any cross-section of a river but they are generally calibrated for certain outlets and give deteriorated results for the sub-catchment outlets. The paper first analyses ISBA-TOP discharge simulations in the French Mediterranean region for target points different from the outlets used for calibration. The sensitivity of the model to its governing factors is examined to highlight the validity of results obtained for ungauged river sections compared with those obtained for the main gauged outlets. The use of improved model inputs is found beneficial for sub-catchments simulation. The calibration procedure however provides the parameters’ values for the main outlets only and these choices influence the simulations for ungauged catchments or sub-catchments. As a result, a new version of ISBA-TOP system without any parameter to calibrate is used to produce diagnostics relevant for quantifying the risk of road submersion. A first diagnostic is the simulated runoff spatial distribution, it provides a useful information about areas with a high risk of submersion. Then an indicator of the flood severity is given by simulated discharges presented with respect to return periods. The latter has to be used together with information about the vulnerability of road-river cross-sections

Circulating Klotho associates with cardiovascular morbidity and mortality during hemodialysis

Epub ahead of printBackground: Klotho gene was identified as an aging suppressor. In animals klotho over-expression extends lifespan and defective klotho results in rapid aging and early death. The kidney is the main contributor to circulating klotho levels and during chronic kidney disease, renal klotho gene expression is drastically reduced in animals and humans as well.Objective: We aimed to determine the consequences of a serum klotho defect on cardiovascular morbidity and mortality during chronic dialysis.Design: The ARNOGENE study was designed to prospectively follow a cohort of hemodialysis patients for 2 years without specific intervention. 769 patients were recruited and followed from the end of 2008 until January 2011. 238 patients were analysed due to a technical sample conservation issue with other samples.Results: The median serum klotho was markedly reduced, 360.4 ng/L [IQR176.5] as compared with non-dialysis chronic kidney disease patients or healthy volunteers. Patients with a serum klotho above the first quartile (≥280 ng/L) had a significantly reduced occurrence of outcome combining cardiovascular events and cardiovascular death (OR=0.39; 0.19-0.78, p=0.008) compared to patient with klotho <280 ng/L. This effect persisted (OR=0.86; 0.76-0.99, p=0.03) after adjustment on age, gender, diabetes, cardiac insufficiency, dialysis vintage, and serum hemoglobin, albumin, FGF-23, phosphate and calcium.Conclusions: These results suggest that during chronic hemodialysis, conservation of serum klotho above 280 ng/L is associated with a better 2-yr cardiovascular protection. Thus, a preserved klotho function supports cardiovascular protection and may represent a prognostic tool and therapeutic target for cardiovascular disease

Evidence for high breakpoint variability in 46, XX, SRY‐positive testicular disorder and frequent ARSE deletion that may be associated with short stature

International audienceBackground: The translocation of SRY onto one of the two X chromosomes results in a 46,XX testicular disorder of sex development; this is supposedly due to non-allelic homologous recombination between the protein kinase X gene (PRKX) and the inverted protein kinase Y pseudogene (PRKY). Although 46,XX SRY-positive men are infertile, the literature data indicate that some of these individuals are of short stature (relative to the general population). We sought to determine whether short stature was linked to additional, more complex chromosomal rearrangements.Methods: Twelve laboratories gathered detailed clinical, anthropomorphic, cytogenetic and genetic data (including chromosome microarray (CMA) data) on patients with 46,XX SRY-positive male syndrome.Results: SRY was present (suggesting a der(X)t(X;Y)) in 34 of the 38 cases (89.5%). When considering only the 20 patients with CMA data, we identified several chromosomal rearrangements and breakpoints - especially on the X chromosome. In the five cases for whom the X chromosome breakpoint was located in the pseudoautosomal (PAR) region, there was partial duplication of the derivate X chromosome. In contrast, in the 15 cases for whom the breakpoint was located downstream of the pseudoautosomal region, part of the derivate X chromosome had been deleted (included the arylsulfatase E (ARSE) gene in 11 patients). For patients with vs. without ARSE deletion, the mean height was respectively 167.7 ± 4.5 and 173.1 ± 4.0 cm; this difference was not statistically significant (p = 0.1005).Conclusion: Although 46,XX SRY-positive male syndromes were mainly due to imbalanced crossover between the X and Y chromosome during meiosis, the breakpoints differed markedly from one patient to another (especially on the X chromosome); this suggests the presence of a replication-based mechanism for recombination between non-homologous sequences. In some patients, the translocation of SRY to the X chromosome was associated with ARSE gene deletion, which might have led to short stature. With a view to explaining this disorder of sex development, whole exome sequencing could be suggested for SRY-negative patients. This article is protected by copyright. All rights reserved

Chromosomal microarray analysis in fetuses with an isolated congenital heart defect: A retrospective, nationwide, multicenter study in France

International audienceObjectives Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD. Methods In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015. Results A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n = 10), 22q11.21 duplications (n = 2), 8p23 deletions (n = 2), an Alagille syndrome (n = 1), and a Kleefstra syndrome (n = 1). Conclusion The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions