Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.

After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed

Syndrome Kabuki (identification de nouveaux paramètres cliniques et biologiques permettant l'amélioration du diagnostic et de la prise en charge)

Le syndrome Kabuki (SK) est caractérisé par des traits morphologiques du visage caractéristiques, des anomalies squelettiques et viscérales, une déficience intellectuelle et un retard de croissance (RC). Son diagnostic reste difficile malgré la découverte récente des bases moléculaire du KS due à des mutations des gènes KMT2D et KDM6A. L'établissement d'un diagnostic étiologique précis permet une prise en charge (PEC) médico·socio·éducative adaptée au patient. L'identification du SK permet de prévenir et de dépister à temps les nombreuses complications associées à ce syndrome (obésité, surdité, manifestations auto-immunes, RC postnatal, déficit en hormone de croissance (GH) et épilepsie). Les objectifs de ce travail sont d'identifier de nouveaux paramètres cliniques et biologiques aidant à l'amélioration du diagnostic et de la PEC. L'atténuation et/ou l'absence congénitale du pli de flexion de l'articulation interphalangienne distale des 3ème et 4ème doigts et la survenue d'un hyperinsulinisme congénital (CHI) dans un contexte syndromique (malformations associées, retard de croissance, microcéphalie, surdité ... ) ont permis respectivement un diagnostic de certitude et le plus précoce possible du SK. Les courbes de croissance spécifiques au KS (poids, taille, périmètre crânien, IMC) et les connaissances sur le CHI (son évolution, son traitement, le risque glycémie perturbée en cas de déficit en GH) sont primordiales pour l'optimisation du suivi des patients avec un dépistage personnalisé. L'utilisation de la Voxel-Based Morphometry pour l'IRM et la translecture des codons stop sont des perspectives d'avenir prometteuses sur le plan de la PEC et de la thérapeutiqueMONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF

Crustal structure and gravity anomalies beneath the Rif, northern Morocco: implications for the current tectonics of the Alboran region

International audienceWe analyse Bouguer anomaly data and previously published Moho depths estimated from receiver functions in order to determine the amount of isostatic compensation or uncompensa-tion of the Rif topography in northern Morocco. We use Moho depth variations extracted from receiver function analyses to predict synthetic Bouguer anomalies that are then compared to observed Bouguer anomaly. We find that Moho depth variations due to isostatic compensation of topographic and/or intracrustal loads do not match Moho depth estimates obtained from receiver function analyses. The isostatic misfit map evidences excess crustal root as large as 10 km in the western part of the study area, whereas a 'missing' crustal root of ∼5 km appears east of 4.3 • E. This excess root/missing topography correlates with the presence of a dense mantle lid, the noticeable southwestward drift of the Western Rif area, and with a current surface uplift. We propose that a delaminated mantle lid progressively detaching westward or southwestward from the overlying crust is responsible for viscous flow of the ductile lower crust beneath the Rif area. This gives rise to isostatic uplift and westward drift due to viscous coupling at the upper/lower crust boundary. At the same time, the presence of this dense sinking mantle lid causes a negative dynamic topography, which explains why the observed topography is too low compared to the crustal thickness

Alu element insertion in the MLH1 exon 6 coding sequence as a mutation predisposing to Lynch syndrome

International audienceLynch syndrome (LS) is the most frequent cause of hereditary colorectal cancer. A subset of patients with a history of LS shows no causal germline pathogenic alteration and are identified as having Lynch‐like syndrome (LLS). Alu retrotransposons are the most abundant mobile DNA sequences in the human genome and have been associated with numerous human cancers by either disrupting coding regions or altering epigenetic modifications or splicing signals. We report a family first classified as having LLS by Sanger sequencing analysis. Next‐generation sequencing (NGS) analysis identified an AluY5a insertion in MLH1 exon 6 that led to exon skipping. This splicing alteration inducing a pathogenic frameshift was found in patients who developed colorectal adenocarcinomas. Retroelement insertion might thus be an important but underestimated mechanism of cancer genetics that could be systematically tested in patients with a phenotype suggesting LS to accurately assess family risk and surveillance approaches

Osteosarcoma without prior retinoblastoma related to RB1 low‐penetrance germline pathogenic variants: A novel type of RB1 ‐related hereditary predisposition syndrome?

International audienceBackground: Retinoblastoma (Rb) is a rare intraocular malignant tumor in childrenwith high overall survival. Predisposition to Rb is linked to RB1 germline mutations with high penetrance, but rare RB1 low‐penetrance variants are also known. Rbsurvivors are at risk of second primary malignancies (SPMs), mostly osteosarcomaand soft‐tissue sarcoma. Nevertheless, the risk of primary osteosarcoma developingwithout prior Rb has not been reported in RB1 germline mutation carriers.Methods: We report a patient in whom osteosarcoma developed at age 17 as a firstprimary malignancy within a family context of sarcoma.Results: Unexpectedly, genetic testing identified a low‐penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup; p.(Pro26Leufs*50)]. In eight additionalsimilar cases from published and unpublished reports of families, first primary osteosarcomas and sarcomas mostly developed in RB1 low‐penetrance mutation carrierswithout prior Rb.Conclusion: We propose that first primary sarcoma and osteosarcoma could bea novel clinical presentation of a RB1‐related hereditary predisposition syndromelinked to RB1 low‐penetrance germline mutations. In these families, careful screening of primary non‐Rb cancer and SPMs is required by maintaining enhanced clinical vigilance. Implementing lifelong periodic whole‐body MRI screening might be acomplementary strategy for unaffected carrier relatives in these families

Osteosarcoma without prior retinoblastoma related to RB1 low‐penetrance germline pathogenic variants: A novel type of RB1‐related hereditary predisposition syndrome?

Abstract Background Retinoblastoma (Rb) is a rare intraocular malignant tumor in children with high overall survival. Predisposition to Rb is linked to RB1 germline mutations with high penetrance, but rare RB1 low‐penetrance variants are also known. Rb survivors are at risk of second primary malignancies (SPMs), mostly osteosarcoma and soft‐tissue sarcoma. Nevertheless, the risk of primary osteosarcoma developing without prior Rb has not been reported in RB1 germline mutation carriers. Methods We report a patient in whom osteosarcoma developed at age 17 as a first primary malignancy within a family context of sarcoma. Results Unexpectedly, genetic testing identified a low‐penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup; p.(Pro26Leufs*50)]. In eight additional similar cases from published and unpublished reports of families, first primary osteosarcomas and sarcomas mostly developed in RB1 low‐penetrance mutation carriers without prior Rb. Conclusion We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a RB1‐related hereditary predisposition syndrome linked to RB1 low‐penetrance germline mutations. In these families, careful screening of primary non‐Rb cancer and SPMs is required by maintaining enhanced clinical vigilance. Implementing lifelong periodic whole‐body MRI screening might be a complementary strategy for unaffected carrier relatives in these families