Schilbach-Rott syndrome (SRS, OMIM%164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild ...mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family. Herein, we investigated by array-CGH analysis a 11-year-old female patient and her father, both exhibiting the typical SRS phenotype, disclosing in the daughter-father couple the same microduplication of chromosome 9q22.32q22.33 arrhg199q22.32(98,049,611_98,049,636)x3,9q22.33 (99,301,483_99,301,508)x3, involving eight genes, including PTCH1. The duplication segregated with the disease, since it was not found in the healthy paternal grandparents of the proband. The gain-of-function variants of the PTCH1 gene are responsible for a mild form of HPE. This is the first genetic variant found in SRS. This finding reinforces the hypothesis that SRS belongs to the HPE clinical spectrum and suggests to perform array-CGH in patients with SRS phenotype and, if negative, to consider a potential benefit from sequencing of HPE-related genes.
Multiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver-Russell (SRS) and Beckwith-Wiedemann (BWS) syndromes. The molecular ...diagnosis of these opposite growth disorders requires a multi-approach flowchart to disclose known primary and secondary (epi)genetic alterations; however, up to 20 and 30 % of clinically diagnosed BWS and SRS cases remain without molecular diagnosis. The complex structure of the 11p15 region with variable CpG methylation and low-rate mosaicism may account for missed diagnoses. Here, we demonstrate the relevance of complementary techniques for the assessment of different CpGs and the importance of testing multiple tissues to increase the SRS and BWS detection rate.
Molecular testing of 147 and 450 clinically diagnosed SRS and BWS cases provided diagnosis in 34 SRS and 185 BWS patients, with 9 SRS and 21 BWS cases remaining undiagnosed and herein referred to as "borderline." A flowchart including complementary techniques and, when applicable, the analysis of buccal swabs, allowed confirmation of the molecular diagnosis in all borderline cases. Comparison of methylation levels by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in borderline and control cases defined an interval of H19/IGF2:IG-DMR loss of methylation that was distinct between "easy to diagnose" and "borderline" cases, which were characterized by values ≤mean -3 standard deviations (SDs) compared to controls. Values ≥mean +1 SD at H19/IGF2: IG-DMR were assigned to borderline hypermethylated BWS cases and those ≤mean -2 SD at KCNQ1OT1: TSS-DMR to hypomethylated BWS cases; these were supported by quantitative pyrosequencing or Southern blot analysis. Six BWS cases suspected to carry mosaic paternal uniparental disomy of chromosome 11 were confirmed by SNP array, which detected mosaicism till 10 %. Regarding the clinical presentation, borderline SRS were representative of the syndromic phenotype, with exception of one patient, whereas BWS cases showed low frequency of the most common features except hemihyperplasia.
A conclusive molecular diagnosis was reached in borderline methylation cases, increasing the detection rate by 6 % for SRS and 5 % for BWS cases. The introduction of complementary techniques and additional tissue analyses into routine diagnostic work-up should facilitate the identification of cases undiagnosed because of mosaicism, a distinctive feature of epigenetic disorders.
In recent years, a rare form of autosomal recessive brachyolmia associated with amelogenesis imperfecta (AI) has been described as a novel nosologic entity. This disorder is characterized by skeletal ...dysplasia (e.g., platyspondyly, short trunk, scoliosis, broad ilia, elongated femoral necks with coxa valga) and severe enamel and dental anomalies. Pathogenic variants in the latent transforming growth factor-β binding protein 3 (
) gene have been found implicated in the pathogenesis of this disorder. So far, biallelic pathogenic
variants have been identified in less than 10 families. We here report a young boy born from consanguineous parents with a complex phenotype including skeletal dysplasia associated with aortic stenosis, hypertrophic cardiomyopathy, hypodontia and amelogenesis imperfecta caused by a previously unreported homozygous
splice site variant. We also compare the genotypes and phenotypes of patients reported to date. This work provides further evidence that brachyolmia with amelogenesis imperfecta is a distinct nosologic entity and that variations in
are involved in its pathogenesis.
Inactivating
mutations causing Sotos syndrome have been previously associated with a specific genome-wide DNA methylation (DNAm) pattern. Sotos syndrome is characterized by phenotypic overlap with ...other overgrowth syndromes, and a definite diagnosis might not be easily reached due to the high prevalence of variants of unknown significance (VoUS) that are identified in patients with a suggestive phenotype.
we performed microarray DNAm profiling in a set of 11 individuals with a clinical suspicion of Sotos syndrome and carrying an
VoUS or previously unreported variants to solve uncertainty in defining pathogenicity of the observed variants. The impact of the training cohort size on sensitivity and prediction confidence of the classifier was assessed.
The Sotos syndrome-specific DNAm signature was validated in six individuals with a clinical diagnosis of Sotos syndrome and carrying
pathogenic
variants. Applying this approach to the remaining 11 individuals with
variants, we succeeded in confirming pathogenicity in eight subjects and excluding the diagnosis of Sotos syndrome in three. The sensitivity and prediction confidence of the classifier based on the different sizes of the training sets did not show substantial differences, though the overall performance was improved by using a data balancing strategy.
The present approach solved uncertainty in cases with
VoUS, further demonstrating the clinical utility of DNAm profiling.
Social media are widely used information tools, including the medical/health field. Unfortunately, the levels of misinformation on these platforms seem to be high, with a medium-low quality of the ...proposed content, as evidenced by previous studies. You Tube is one of the most important platforms for audio/video content. It shows content to users through a recommendation algorithm system.
We have classified in two cohorts the first results obtained by researching "bladder tumor treatment" on You Tube through two different user profiles: "Cohort A" with a not logged-in session in incognito mode (46 videos enrolled) and "Cohort B" with a logged-in session with a physician profile (50 videos enrolled). The videos were evaluated using validated instruments such as DISCERN and PEMAT-AV Furthermore, we used a Likert's scale for the evaluation of levels of misinformation.
Overall quality of information was moderate to poor (DISCERN 3) in 54% of Cohort A and 24% of Cohort B. Moreover, a high degree of misinformation (Likert score 3) was found in 52% of Cohort A cases and 32% of Cohort B.
Levels of misinformation in both cohorts are positively correlated to the number of views per month. Globally, the levels of information quality, understandability and actionability are lower for the results obtained from searches performed with anonymous user profile (Cohort A).
Heterozygous mutations in the
gene or in the upstream and downstream enhancer elements are associated with 2-22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of ...Leri-Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80-90% of
pathogenic variants are deletions or duplications, and the remaining 10-20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance. Here, we describe a novel missense variant (c.1044 G>T, p.Arg118Met) in a Moroccan boy with a disproportionately short stature and without any radiological traits or bone deformities and in his mother, who had a disproportionately short stature and a Madelung deformity. This variant has not been reported to date in the updated
allelic variant or Human Gene Mutation Databases nor is it listed as a polymorphism in the ExAC browser, dbSNP, or 1000G. This mutation was predicted to be deleterious by three different bioinformatics tools since it modifies an amino acid in a highly conserved DNA-binding domain of the SHOX protein. Based on this evidence, the patient was treated with recombinant human growth hormone.
To evaluate surgical outcomes in a series of laparoscopic retroperitoneal partial nephrectomies.
A total of 147 patients who underwent laparoscopic retroperitoneal partial nephrectomy by a single ...surgeon were evaluated. Pre-operative parameters (body mass index, ASA score, tumour size, cTNM stage, PADUA score risk, surgeon experience) and intraoperative and postoperative outcomes (operative mean time, warm ischemia time, blood loss, transfusion rate, length of hospitalization, and margin-ischaemiacomplications MIC success rate) were considered.
For 134 patients (91.1%) the success of the treatment, defined by a MIC = 3, was obtained. When the statistical significance of each of the independent variables was tested, surgeon's experience added statistical significance to the prediction of operative time (p = 0.000), warm ischemia time (p = 0.000) and blood loss (p = 0.000); tumour size (p = 0.046) to the prediction MIC (p = 0.010), operative time (p = 0.000), warm ischemia time (p = 0.003) and blood loss (p = 0.010); ASA score to the length of hospitalization (p = 0.009).
Laparoscopic retroperitoneal partial nephrectomy represents an adequate and safe technique for the treatment of T1 renal cancer. Optimal MIC success rate can be achieved, although intraoperative outcomes tend to be related to the learning curve even in a very experienced laparoscopic surgeon. Length of hospitalization depends on general health condition of patients.
Deletion 2p15–16.1 syndrome: Case report and review Prontera, Paolo; Bernardini, Laura; Stangoni, Gabriela ...
American journal of medical genetics. Part A,
October 2011, Volume:
155, Issue:
10
Journal Article
Arterio-ureteralfistula (AUF) is an infrequent but potentially life-threatening condition. The aim of this study was reviewing the literature to build a flow-chart useful for an early and effective ...diagnosis and treatment of this pathology.
A literature search in PubMed was conducted. In addition, retrieved articles were cross-referenced. Data parameters included oncologic, vascular and urological history, diagnostics, treatment, and follow up were collected using a standard template by 2 independent reviewers.
A total of 140 cases of AUF out of 172 available in the literature at the time of the review, were considered. All patients presented gross hematuria. Chronic indwelling ureteral catheter (CIUC); history of pelvic surgery (HPS) and history of pelvic radiotherapy (HRT) were present respectively in 81%, 62.1%and 58.6% of the sample. The most predominant location of AUF was at the common iliac artery ureteral crossing. Angiography with provocative measures had the highest diagnostic sensitivity (50%) and endovascular treatment with stent-graft placement across the fistula is the current state of the art treatment choice.
Failure to diagnose can postpone a potentially life-saving targeted therapy and lead to complications. The identifi-cation of the Trifecta hematuria, history of pelvic surgery (HPS) and history of pelvic radiotherapy (HPR) would allow the identity-fication of patients at high risk of AUF, who may benefit from more sensitive early diagnostic investigations such as CT angiography and provocative angiography. The treatment of choice in case of AUF to date consist in endovascular prosthesis placement.
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