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Purpose Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusion Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

ObjectiveThe purpose of this study was to describe reports of congenital eye anomalies entered in the international pharmacovigilance database, with a particular focus on medications associated with this type of anomaly.Methods and analysisThis descriptive, retrospective study selected reports using the adverse reaction term ‘congenital eye disorders’ and included only those instances where at least one medication was documented as being administered via the transplacental route. Statistical analyses were performed using R software.ResultsWe extracted 2923 reports of eye anomalies in children exposed to medications in utero and ultimately selected 676 of these. Congenital anomalies of the eyelids (17.3%), lacrimal apparatus (9.4%) and orbit (1.1%) were the most common. The suspect medications highlighted in this study include teratogenic agents known to pose a risk of triggering eye anomalies such as valproic acid and mycophenolic acid. The list also includes medications with little or no reference in the literature to potential eye anomalies following in utero exposure, such as hydroxychloroquine and ondansetron.ConclusionThis study provides new data on in utero exposure to medications and congenital eye anomalies that can be severely debilitating. This is a descriptive study, with all the inherent limitations of the pharmacovigilance databases which are used for signal detection. This descriptive study does not allow us to conclude that there is a causal link between exposure to a given medication during pregnancy and congenital eye anomalies and is a basis for future studies using different data sources and/or other methods.

The cytopathology of salivary glands presents major challenges due to the heterogeneity of benign and malignant neoplasms, which is reflected in the large range of WHO 2017 Classifications. Fine needle aspiration (FNA) of salivary gland tumours is still the favoured initial approach as it results in good sensitivity and specificity. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was published in 2018 and comprises seven categories. We report results from a 4-year retrospective analysis of 328 salivary gland FNAs which were reviewed and classified according to the MSRSGC. We assess the risk of neoplasm, the risk of malignancy and the contribution of ancillary studies to the diagnosis. Benign neoplasms were the most frequent diagnosis (44.2%). Malignant and suspicious for malignancy were identified in 11.3% and 4.9% of diagnosed cases, respectively. Histopathological analysis after surgery was available for 216 (65.8%) of the cases. All malignant cases were confirmed post-surgery, and 68.8% of suspicious for malignancy were confirmed as malignant tumours. Immunocytochemistry was informative in 72.3% of cases. Immunocytochemistry and FISH provided the definitive diagnosis in 23.7% and 33% of cases, respectively. In conclusion, the MSRSGC is more effective when specific features of neoplasms can be identified. Ancillary studies help to further characterise salivary gland tumours and thereby increase the accuracy of MSRSGC.

Estrogens, mainly 17β-estradiol (E2), play a critical role in reproductive organogenesis, ovulation, and fertility via estrogen receptors. E2 is also a well-known regulator of utero-placental vascular development and blood-flow dynamics throughout gestation. Mouse and human placentas possess strikingly different morphological configurations that confer important reproductive advantages. However, the functional interplay between fetal and maternal vasculature remains similar in both species. In this review, we briefly describe the structural and functional characteristics, as well as the development, of mouse and human placentas. In addition, we summarize the current knowledge regarding estrogen actions during utero-placental vascular morphogenesis, which includes uterine angiogenesis, the control of trophoblast behavior, spiral artery remodeling, and hemodynamic adaptation throughout pregnancy, in both mice and humans. Finally, the estrogens that are present in abnormal placentation are also mentioned. Overall, this review highlights the importance of the actions of estrogens in the physiology and pathophysiology of placental vascular development.

We present two types of FBT for which diagnostic orientation was initially erroneous because of the challenging antenatal diagnosis of FBT. Autopsy enabled to rectify the initial antenatal diagnosis and establish the FBT phenotypic profile.

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We report here about two novel tumours classified as extraventricular neurocytomas (EVN) using DNA‐methylation profiling, associated with NTRK2 fusions instead of the usual FGFR1 alterations so far attributed to this tumoural entity. We present the second detailed case of an intraventricular presentation in the MC EVN. Our findings broaden the spectrum of MC EVN and have implications in terms of diagnosis, therapy and terminology.

PurposeWide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID).MethodsFrom 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018).ResultsMMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%).ConclusionMMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling.

BackgroundEllis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib–polydactyly subgroup. Major signs are ectodermal dysplasia, chondrodysplasia, polydactyly and congenital cardiopathy, with a high degree of variability in phenotypes ranging from lethal to mild clinical presentations. The EVC and EVC2 genes are the major genes causative of EVC syndrome. However, an increased number of genes involved in the ciliopathy complex have been identified in EVC syndrome, leading to a better understanding of its physiopathology, namely, WDR35, GLI1, DYNC2LI1, PRKACA, PRKACB and SMO. They all code for proteins located in the primary cilia, playing a key role in signal transduction of the Hedgehog pathways.MethodsThe aim of this study was the analysis of 50 clinically identified EVC cases from 45 families to further define the phenotype and molecular bases of EVC.ResultsOur detection rate in the cohort of 45 families was of 91.11%, with variants identified in EVC/EVC2 (77.8%), DYNC2H1 (6.7%), DYNC2LI1 (2.2%), SMO (2.2%) or PRKACB (2.2%). No distinctive feature was remarkable of a specific genotype–phenotype correlation. Interestingly, we identified a high proportion of heterozygous deletions in EVC/EVC2 of variable sizes (26.92%), mostly inherited from the mother, and probably resulting from recombinations involving Alu sequences.ConclusionWe confirmed that EVC and EVC2 are the major genes involved in the EVC phenotype and highlighted the high prevalence of previously unreported CNVs (Copy Number Variation).