scholarly journals Novel mutations in NOTCH2 gene in infants with neonatal cholestasis

2019 ◽  
Vol 11 (3) ◽  
Author(s):  
Eliana Shaul ◽  
Debora Kogan-Liberman ◽  
Stephanie Schuckalo ◽  
Dominique Jan ◽  
Michelle Ewart ◽  
...  
Keyword(s):  
Case Series ◽  
Alagille Syndrome ◽  
Notch Signaling Pathway ◽  
Clinical Approach ◽  
Neonatal Cholestasis ◽  
Retrospective Case ◽  
Variants Of Unknown Significance ◽  
Intrahepatic Bile Ducts ◽  
Sorting Intolerant From Tolerant ◽  
Unknown Significance

One cause of neonatal cholestasis (NC) is paucity of intrahepatic bile ducts which can be associated with Alagille syndrome or non- syndromic. Alagille syndrome is caused by autosomal dominant mutations in the Notch signaling pathway ligand Jagged1 in 94% of patients and mutations in the NOTCH2 receptor in <1% of patients. This is a retrospective case series studying infants with neonatal cholestasis found to have variants of unknown significance (VOUS) in NOTCH2. Sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen) were utilized to predict a damaging effect. Five infants with NC without other features of Alagille syndrome were found to have one copy of a VOUS in NOTCH2, predicted to be damaging by SIFT and PolyPhen. Our cases support the notion that NOTCH2 mutations may result in hypoplastic biliary system. Further characterization of these variants is important to assist with our clinical approach to NC.

scholarly journals Hyperferritinemia in patients with nonalcoholic fatty liver disease

2017 ◽  
Vol 63 (3) ◽  
pp. 284-289 ◽  
Author(s):  
Raffaelle K Barros ◽  
Helma Pinchemel Cotrim ◽  
Carla H Daltro ◽  
Yanaihara A Oliveira
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Liver Diseases ◽  
Elevated Serum ◽  
Case Series ◽  
Clinical Approach ◽  
Retrospective Case ◽  
Nonalcoholic Fatty Liver

Summary Objective: In liver diseases, hyperferritinemia (HYF) is related to injured cells in acquired and genetic conditions with or without iron overload. It is frequent in patients with nonalcoholic fatty liver disease (NAFLD), in which it is necessary to define the mean of HYF to establish the better approach for them. The present study evaluated the significance of elevated ferritin in patients with NAFLD and steatohepatitis (NASH). Method: The review was performed using search instruments of indexed scientific material, including MEDLINE (by PubMed), Web of Science, IBECS and LILACS, to identify articles published in Portuguese, English and Spanish, from 2005 to May, 2016. Studies eligible included place and year of publication, diagnose criteria to NAFLD, specifications of serum ferritin measurements and/or liver histopathologic study. Exclusion criteria included studies with patients with alcohol consumption ≥ 20 g/day and other liver diseases. Results: A total of 11 from 30 articles were selected. It included 3,564 patients and they were cross-sectional, retrospective, case series and case-control. The result's analyses showed in 10 of these studies a relationship between ferritin elevated serum levels and NAFLD/NASH with and without fibrosis and insulin resistance. Conclusion: Hyperferritinemia in patients with NAFLD/NASH is associated more frequently with hepatocellular injury than hemochromatosis. These data suggest the relevance to evaluate carefully HYF in patients with NAFLD/NASH to establish appropriate clinical approach.

scholarly journals In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kok-Siong Poon
Keyword(s):  
Genetic Testing ◽  
Molecular Genetic ◽  
In Silico Analysis ◽  
Molecular Testing ◽  
Brca1 And Brca2 ◽  
Missense Variants ◽  
Variants Of Unknown Significance ◽  
Sorting Intolerant From Tolerant ◽  
Unknown Significance ◽  
High Concordance

AbstractOver the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant from Tolerant (SIFT) are two widely applied bioinformatics tools used to assess the functional impacts of missense variants. A total of 2605 BRCA1 and 4763 BRCA2 variants from the ClinVar database were analysed with PolyPhen2 and SIFT. When SIFT was evaluated alongside PolyPhen-2 HumDiv and HumVar, it had shown top performance in terms of negative predictive value (NPV) (100%) and sensitivity (100%) for ClinVar classified benign and pathogenic BRCA1 variants. Both SIFT and PolyPhen-2 HumDiv achieved 100% NPV and 100% sensitivity in prediction of pathogenicity of the BRCA2 variants. Agreement was achieved in prediction outcomes from the three tested approaches in 55.04% and 68.97% of the variants of unknown significance (VUS) for BRCA1 and BRCA2, respectively. The performances of PolyPhen-2 and SIFT in predicting functional impacts varied across the two genes. Due to lack of high concordance in prediction outcomes among the two tested algorithms, their usefulness in classifying the pathogenicity of VUS identified through molecular testing of BRCA1 and BRCA2 is hence limited in the clinical setting.

scholarly journals Interpreting Osteogenesis Imperfecta Variants of Uncertain Significance in the Context of Physical Abuse: A Case Series

2018 ◽  
Vol 08 (02) ◽  
pp. 063-068
Author(s):  
Jennifer Canter ◽  
Vinod Rao ◽  
Vincent Palusci ◽  
David Kronn ◽  
Michal Manaster ◽  
...  
Keyword(s):  
Child Abuse ◽  
Osteogenesis Imperfecta ◽  
Physical Abuse ◽  
Clinical Significance ◽  
Case Series ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Potential Abuse ◽  
Uncertain Significance

AbstractUnexplained childhood fracture(s) warrant consideration of physical abuse and osteogenesis imperfecta (OI). Genetic OI testing may identify “variants of unknown significance (VUS).” Interpretation of VUS in context of potential abuse may have protective, criminal, and medical impacts. This case series explores practices regarding clinicians' interpretation of VUS during child abuse evaluations. Variability was noted regarding factors considered for interpreting clinical significance. Based on these cases, recommendations for careful and thorough evaluation are detailed, including proposed use of a limited follow-up skeletal survey in 3 months, as a consideration to assess healing of prior fractures and to look for any additional injuries.

scholarly journals A Novel c.91dupG JAG1 Gene Mutation Is Associated with Early Onset and Severe Alagille Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Alejandra del Pilar Reyes-de la Rosa ◽  
Gustavo Varela-Fascinetto ◽  
Constanza García-Delgado ◽  
Edgar Ricardo Vázquez-Martínez ◽  
Pedro Valencia-Mayoral ◽  
...  
Keyword(s):  
De Novo ◽  
Pulmonary Stenosis ◽  
Gene Mutations ◽  
Alagille Syndrome ◽  
Notch Signaling Pathway ◽  
Heterozygous Mutation ◽  
Sequencing Analysis ◽  
Autosomal Dominant Disorder ◽  
Intrahepatic Bile Ducts ◽  
Chronic Cholestasis

Alagille syndrome (MIM 118450) is an autosomal dominant disorder characterized by paucity of intrahepatic bile ducts, chronic cholestasis, pulmonary stenosis, butterfly-like vertebrae, posterior embryotoxon, and dysmorphic facial features. Most cases are caused by JAG1 gene mutations. We report the case of a 2-year-old Mexican mestizo patient with Alagille syndrome, having exhibited jaundice and cholestatic syndrome as of three weeks of age. Sequencing analysis of the JAG1 gene revealed the novel heterozygous mutation c.91dupG that originates a truncated protein and therefore a possibly diminished activation of the Notch signaling pathway. The latter may explain the severe phenotype of the patient. Since the mutation was not identified in the parents, it was considered a de novo event, highlighting the importance of molecular diagnosis and genetic counseling. In conclusion, this report widens the spectrum of JAG1 gene mutations associated with Alagille syndrome.

Alagille Syndrome: An Overview

2017 ◽  
Vol 36 (6) ◽  
pp. 343-347 ◽  
Author(s):  
Dalacy Jesina
Keyword(s):  
Autosomal Dominant ◽  
Pulmonary Stenosis ◽  
Alagille Syndrome ◽  
Notch Signaling Pathway ◽  
Autosomal Dominant Disorder ◽  
Vascular Events ◽  
Variable Expression ◽  
Intrahepatic Bile Ducts ◽  
Improved Outcomes ◽  
Detection And Diagnosis

AbstractAlagille syndrome (AGS) is a highly complex, multisystem, autosomal dominant disorder that is caused by a defect in the Notch signaling pathway. This syndrome mainly affects the liver, causing significant cholestasis, which is caused by a paucity of intrahepatic bile ducts. There can be cardiac involvement, including, but not limited to, pulmonary stenosis and tetralogy of Fallot. Patients can also present with butterfly vertebra, ocular issues, and vascular events. Because this syndrome follows an autosomal dominant inheritance, it can have variable expression even in the same family line. For infants in the NICU who have a cardiac defect and persistent hyperbilirubinemia after two weeks of age, genetic testing for AGS should be considered. Early detection and diagnosis can lead to improved outcomes. In this discussion of AGS, the clinical features as well as management are discussed.

Management of isoniazid-monoresistant tuberculosis (Hr-TB) in Queensland, Australia: a retrospective case series

2020 ◽  
Vol 173 ◽  
pp. 106163
Author(s):  
Malcolm Wilson ◽  
Bridget O'Connor ◽  
Nicholas Matigian ◽  
Geoffrey Eather
Keyword(s):  
Case Series ◽  
Retrospective Case ◽  
Retrospective Case Series

scholarly journals Peripartum hysterectomy: a five year review at a tertiary care centre

2017 ◽  
Vol 6 (8) ◽  
pp. 3590
Author(s):  
Deepak A. V. ◽  
K. J. Jacob ◽  
Sumi P. Maria
Keyword(s):  
Tertiary Care ◽  
Case Series ◽  
Case Fatality ◽  
Tertiary Care Centre ◽  
Retrospective Case ◽  
College Hospital ◽  
Peripartum Hysterectomy ◽  
Medical College ◽  
Obstetric Haemorrhage ◽  
Suboptimal Care

Background: Peripartum hysterectomy is a life-saving procedure resorted to when conservative measures fail to control obstetric haemorrhage. Several predisposing factors, suboptimal care and lack of infrastructure may lead to this emergency procedure. We wanted to find out factors associated with peripartum hysterectomy and the adverse maternal outcomes at our centre.Methods: A retrospective case series analysis of 40 cases of peripartum hysterectomy performed over a period of 5 years from January 2010 to December 2014 at Government Medical College Hospital, Thrissur, Kerala was done.Results: The incidence of peripartum hysterectomy was 0.29%. The most common indication for peripartum hysterectomy was hysterectomy was uterine atony (50%). Thirty-five women (88%) were between 20 and 35 years. Most of the subjects were unbooked. There were two maternal deaths (case fatality rate of 5%) following peripartum hysterectomy during this period. All the subjects required blood transfusion.Conclusions: Prompt performance hysterectomy before the patient’s clinical condition deteriorates is the key to success. The incidence of adherent placenta is increasing, so every effort should be taken to reduce the caesarean section rates globally. 

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