A child without kneecaps

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Two further patients with Warsaw breakage syndrome. Is a mild phenotype possible?

Background: Warsaw Breakage Syndrome (WABS) is an ultra rare cohesinopathy caused by biallelic mutation of DDX11 gene. It is clinically characterized by pre and postnatal growth delay, microcephaly, hearing loss with cochlear hypoplasia, skin color abnormalities, and dysmorphisms. Methods: Mutational screening and functional analyses (protein expression and 3D-modeling) were performed in order to investigate the presence and pathogenicity of DDX11 variant identified in our patients. Results: We report the clinical history of two sisters affected by WABS with a pathological mytomicin C test carrying compound heterozygous mutations (c.2507T > C / c.907_920del) of the DDX11 gene. The pathogenicity of this variant was confirmed in the light of a bioinformatic study and protein three-dimensional modeling, as well as expression analysis. Conclusion: These findings further extend the clinical and molecular knowledge about the WABS showing a possible mild phenotype without major malformations or intellectual disability

A bird’s eye view on the use of whole exome sequencing in rare congenital ophthalmic diseases

Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and classification of diseases. Over the last decade, genomic research has indeed boosted our understanding in the molecular basis of ASD and genes associated with both autosomal dominant and recessive patterns of inheritance have been described with a wide range of expressivity. Here we describe the molecular characterization of a cohort of 162 patients displaying isolated or syndromic congenital ocular dysgenesis. Samples were analyzed with diverse techniques, such as direct sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing (WES), over 20 years. Our data reiterate the notion that PAX6 alterations are primarily associated with ASD, mostly aniridia, since the majority of the cohort (66.7%) has a pathogenic or likely pathogenic variant in the PAX6 locus. Unexpectedly, a high fraction of positive samples (20.3%) displayed deletions involving the 11p13 locus, either partially/totally involving PAX6 coding region or abolishing its critical regulatory region, underlying its significance. Most importantly, the use of WES has allowed us to both assess variants in known ASD genes (i.e., CYP1B1, ITPR1, MAB21L1, PXDN, and PITX2) and to identify rarer phenotypes (i.e., MIDAS, oculogastrointestinal-neurodevelopmental syndrome and Jacobsen syndrome). Our data clearly suggest that WES allows expanding the analytical portfolio of ocular dysgenesis, both isolated and syndromic, and that is pivotal for the differential diagnosis of those conditions in which there may be phenotypic overlaps and in general in ASD

Melorheostosis and Osteopoikilosis Clinical and Molecular Description of an Italian Case Series

Melorheostosis (MEL) is an uncommon, sclerosing disease, characterised by hyperostosis of long bones, resembling the flowing of candle wax. The disease is sporadic and the pathogenesis is still poorly understood. Occasionally, the same family can include individuals with MEL and Osteopoikilosis (OPK), a disease characterised by multiple round foci of increased bone density. LEMD3 gene mutations are related to OPK and Buschke\u2013Ollendorff Syndrome, a genetic condition in which an association between MEL, OPK and skin lesions is observed. In rare cases, LEMD3 mutations and recently mosaic MAP2K1 gene mutations have been correlated to MEL suggesting that somatic mosaicism could be causative of the disease. In this study, we described the clinical, radiological and molecular findings of 19 individuals with MEL and 8 with OPK and compared the results to the medical literature. The molecular analyses of this case series corroborate the available data in the medical literature, indicating that LEMD3 germline mutations are not a major cause of isolated MEL and reporting five further cases of OPK caused by LEMD3 germline mutations

Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans and the majority of patients carry a variant in either PKD1 or PKD2. Genetic testing is increasingly required for diagnosis, prognosis, and treatment decision, but it is challenging due to segmental duplications of PKD1, genetic and allelic heterogeneity, and the presence of many variants hypomorphic or of uncertain significance. We propose an NGS-based testing strategy for molecular analysis of ADPKD and its phenocopies, validated in a diagnostic setting. Materials and Methods: Our protocol is based on high-throughput simultaneous sequencing of PKD1 and PKD2 after long range PCR of coding regions, followed by a masked reference genome alignment, and MLPA analysis. A further screening of additional 14 cystogenes was performed in negative cases. We applied this strategy to analyze 212 patients with a clinical suspicion of ADPKD. Results and Discussion: We detected causative variants (interpreted as pathogenic/likely pathogenic) in 61.3% of our index patients, and variants of uncertain clinical significance in 12.5%. The majority (88%) of genetic variants was identified in PKD1, 12% in PKD2. Among 158 distinct variants, 80 (50.6%) were previously unreported, confirming broad allelic heterogeneity. Eleven patients showed more than one variant. Segregation analysis indicated biallelic disease in five patients, digenic in one, de novo variant with unknown phase in two. Furthermore, our NGS protocol allowed the identification of two patients with somatic mosaicism, which was undetectable with Sanger sequencing. Among patients without PKD1/PKD2 variants, we identified three with possible alternative diagnosis: a patient with biallelic mutations in PKHD1, confirming the overlap between recessive and dominant PKD, and two patients with variants in ALG8 and PRKCSH, respectively. Genotype-phenotype correlations showed that patients with PKD1 variants predicted to truncate (T) the protein experienced end-stage renal disease 9 years earlier than patients with PKD1 non-truncating (NT) mutations and >13 years earlier than patients with PKD2 mutations. ADPKD-PKD1T cases showed a disease onset significantly earlier than ADPKD-PKD1NT and ADPK-PKD2, as well as a significant earlier diagnosis. These data emphasize the need to combine clinical information with genetic data to achieve useful prognostic predictions

Multidetector CT imaging of mechanical prosthetic heart valves: quantification of artifacts with a pulsatile in-vitro model

Item does not contain fulltextOBJECTIVES: Multidetector computed tomography (MDCT) can detect the cause of prosthetic heart valve (PHV) dysfunction but is hampered by valve-induced artifacts. We quantified artifacts of four PHV using a pulsatile in-vitro model and assessed the relation to leaflet motion and valve design. METHODS: A Medtronic Hall tilting disc (MH), and Carbomedics (CM), St Jude (SJM), and ON-X bileaflet valves underwent CT in an in-vitro model using retrospective gating with a 64 detector CT system in stationary and pulsatile conditions. Artifacts and radiopaque component volumes were quantified with thresholds based on surrounding structures and valvular components. RESULTS: Hypodense artifacts volumes (mm(3)) were 1,029 +/- 147, 535 +/- 53, 371 +/- 16, and 366 +/- 18 for the SJM, MH, CM and ON-X valves (p < 0.001 except for the latter two valves p = 0.43). Hyperdense artifact volumes were 3,546 +/- 141, 2,387 +/- 103, 2,003 +/- 102, and 3,033 +/- 31 for the SJM, MH, CM and ON-X valve, respectively (all differences p < 0.001). Leaflet motion affected hypodense (F = 41.5, p < 0.001) and hyperdense artifacts (F = 53.7, p < 0.001). Closed and moving leaflets were associated with the least and the most artifacts respectively (p < 0.001, both artifact types). CONCLUSION: Both valve design and leaflet motion affect PHV-induced artifacts. Best imaging results may be expected for the CM valve during phases in which the leaflets are closed

Expanding Phenotype of Poirier\u2013Bienvenu Syndrome: New Evidence from an Italian Multicentrical Cohort of Patients

Background: Poirier\u2013Bienvenu Neurodevelopmental Syndrome (POBINDS) is a rare disease linked to mutations of the CSNK2B gene, which encodes for a subunit of caseinkinase CK2 involved in neuronal growth and synaptic transmission. Its main features include early-onset epilepsy and intellectual disability. Despite the lack of cases described, it appears that POBINDS could manifest with a wide range of phenotypes, possibly related to the different mutations of CSNK2B. Methods: Our multicentric, retrospective study recruited nine patients with POBINDS, detected using next-generation sequencing panels and whole-exome sequencing. Clinical, laboratory, and neuroimaging data were reported for each patient in order to assess the severity of phenotype, and eventually, a correlation with the type of CSNK2B mutation. Results: We reported nine unrelated patients with heterozygous de novo mutations of the CSNK2B gene. All cases presented epilepsy, and eight patients were associated with a different degree of intellectual disability. Other features detected included endocrinological and vascular abnormalities and dysmorphisms. Genetic analysis revealed six new variants of CSNK2B that have not been reported previously. Conclusion: Although it was not possible to assess a genotype\u2013phenotype correlation in our patients, our research further expands the phenotype spectrum of POBINDS patients, identifying new mutations occurring in the CSNK2B gene

Prospective ECG triggering reduces prosthetic heart valve-induced artefacts compared with retrospective ECG gating on 256-slice CT

Item does not contain fulltextOBJECTIVES: Multidetector computed tomography (MDCT) has diagnostic value for the evaluation of prosthetic heart valve (PHV) dysfunction but it is hampered by artefacts. We hypothesised that image acquisition using prospective triggering instead of retrospective gating would reduce artefacts related to pulsating PHV. METHODS: In a pulsatile in vitro model, a mono- and bileaflet PHV were imaged using 256 MDCT at 60, 75 and 90 beats per minute (BPM) with either retrospective gating (120 kV, 600 mAs, pitch 0.2, CTDI(vol) 39.8 mGy) or prospective triggering (120 kV, 200 mAs, CTDI(vol) 13.3 mGy). Two thresholds (>175 and <-45HU), derived from the density of surrounding structures, were used for quantification of hyper- and hypodense artefacts. Image noise and artefacts were compared between protocols. RESULTS: Prospective triggering reduced hyperdense artefacts for both valves at every BPM (P = 0.001 all comparisons). Hypodense artefacts were reduced for the monoleaflet valve at 60 (P = 0.009), 75 (P = 0.016) and 90 BPM (P = 0.001), and for the bileaflet valves at 60 (P = 0.001), 90 (P = 0.001) but not at 75 BPM (P = 0.6). Prospective triggering reduced image noise at 60 (P = 0.001) and 75 (P < 0.03) but not at 90 BPM. CONCLUSIONS: Compared with retrospective gating, prospective triggering reduced most artefacts related to pulsating PHV in vitro. KEY POINTS: * Computed tomographic images are often degraded by prosthetic heart valve-induced artefacts * Prospective triggering reduces prosthetic heart valve-induced artefacts in vitro * Artefact reduction at 90 beats per minute occurs without image noise reduction * Prospective triggering may improve CT image quality of moving hyperdense structures.1 juni 201