Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

A novel chest CT severity score in COVID-19 and its correlation with severity and prognosis of the lung disease: A retrospective cohort study.

Background: HRCT chest has a high sensitivity in the diagnosis of patients with COVID-19 infection. Through our study, we intend to evaluate the diagnostic accuracy and inter-reader variability of a semi-quantitative CT severity score, a novel parameter designed for risk stratification and prognostication of COVID-19 pneumonia with clinical staging of disease. Methods: It was a single-center retrospective analysis performed on an original cohort of 4180 symptomatic patients with the suspicion of SARS-CoV-2 interstitial pneumonia. Out of 4180, a total of 4004 patients with COVID-19 were confirmed by an RT-PCR. We used an HRCT chest severity score (CT-SS) to evaluate the COVID-19 disease burden on the initial scan obtained at admission. The data were analyzed with IBM SPSS Statistics Version 22.0 Release 2013. Results: Our study subjects demonstrated the most common clinical features fever, cough, dyspnea, and body aches. Raised CRP levels (CRP >0.5 mg/dL) were found in 81.86% and increased D-dimer levels (>500 ng/mL) were found in 92.3% of patients. The most common radiological findings of the disease included ground-glass opacities, observed in 98.8%. Our study has a sensitivity of 89.2%, a specificity of 94.8%, a positive predictive value (PPV) of 90.6%, and a negative predictive value (NPV) of 94%. Conclusion: As per our findings, this novel CT scoring system might aid in the risk stratification and the short-term prognostication of patients suffering from COVID-19 pneumonia. This will eventually help in curtailing the extensive burden on the healthcare system amid the current pandemic.

Rare pathogenic mutation in the thymidine phosphorylase gene (TYMP) causing mitochondrial neurogastrointestinal encephalomyelopathy.

Background: Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is a rare multisystem disorder that mainly affects the digestive and nervous systems. Key features of the disease include cachexia, ptosis, external ophthalmoplegia, peripheral neuropathy and leucoencephalopathy. Symptoms most often begin by age 20 and overlap several other Metabolic and endocrine disorders making the diagnosis challenging. It has been determined that MNGIE is caused by mutations in the gene-encoding thymidine phosphorylase (TP; previously known as endothelial cell growth factor 1). Case: We herein present the clinical, neuroimaging and molecular findings in a patient with MNGIE caused by a novel homozygous variant of TYMP gene c.1048C>T, which is predicted to result in a premature protein termination (p.Gln350*). TYMP is a gene on chromosome 22q13.33 that encodes TP. Conclusion: This case highlights the importance of good understanding and early recognition of a rare condition like MNGIE, so that the suffering from unnecessary interventional procedures can be avoided and better multidisciplinary care can be implemented for the symptomatic management of the patient.

Anabolic-androgenic steroid use in a young body-builder: A case report and review of the literature.

Introduction: Anabolic-androgenic steroid (AAS) abuse is routine in athletes to enhance their overall physique. It often leads to detrimental effects, including cardiovascular diseases, hormonal imbalances, and cancer. Our case presentation emphasizes two important aspects: the first is the importance of thorough history taking in correctly diagnosing diseases with multiple etiologies. The second one relates to the reversible and preventable hazards of the increasing incidence of usage of illicit drugs, mainly androgenic anabolic steroids in young adults. Case presentation: We present a case of a 30-year-old male bodybuilder with presenting complaints of increased anxiousness, excessive anger, and dyspnea on minimal exertion. Echocardiogram showed a dilated cardiomyopathy with left ventricular ejection fraction (LVEF) of 20%. The patient was counseled for quitting AAS and symptomatically treated on heart failure management guidelines. He responded well to the management plan and now enjoying a healthy life. Conclusion: It is imperative to raise awareness regarding the substantial adverse effects of AAS abuse that might precipitate severe cardiovascular system complications leading to morbidity and eventual mortality. Most of the times, the pathological changes due to AAS abuse are reversible. This shows a good prognosis and better compliance with the management plan advised to the patients.

The Promising Future of Low-Molecular-Weight Heparin in Pediatric Cerebral Venous Sinus Thrombosis Occurring as a Rare Complication of Ulcerative Colitis.

Pediatric cerebral venous sinus thrombosis (CVST) is a rare complication of ulcerative colitis. Ulcerative colitis is a form of inflammatory bowel disease which accentuates hypercoagulation, thereby leading to thrombosis. Herein, we report a case of a 10-year-old girl who presented with chief complaints of headache, confusion, and new-onset seizure activity for one month as progressively worsening sequelae of ulcerative colitis. Her magnetic resonance venogram confirmed thrombosis in the right transverse, sigmoid, and superior sagittal sinus. The acute ulcerative colitis flare was managed with a short course of steroids and anti-inflammatory monoclonal antibody, and CVST got improved with low-molecular-weight heparin (LMWH). Our study emphasizes the emergence of fatal complications of ulcerative colitis in the pediatric population. It also endorses the pivotal role of thromboprophylaxis with LMWH in pediatric CVST patients. Nevertheless, further studies are required to standardize the use of LMWH in clinical practice.

Association of quality of life, anxiety, and depression with restless leg syndrome in the hemodialysis patients.

OBJECTIVES: Restless Legs Syndrome (RLS) is commonly known to cause morbidity in patients on hemodialysis, making them prone to chronic mental health illnesses such as depression and anxiety, and also adversely impact quality of life. In this study, we examined the association of quality of life, anxiety, and depression with restless leg syndrome in the hemodialysis patients at Karachi Institute of Kidney Diseases. RESULTS: About 26.7% of the participants reported RLS among the sample size Presence of RLS was not associated with quality of life, depression, and anxiety. However, p-values < 0.05 were significant for body-mass index (BMI), diabetes mellitus as a cause of end-stage renal disease, and serum albumin levels. Majority (82.5%) of the RLS-diagnosed patients had moderate to severe symptoms with 16 (40%) and 17 (42.5%) clients, respectively.

Fibroblast Growth Factor 21 and Its Association With Oxidative Stress and Lipid Profile in Type 2 Diabetes Mellitus.

Introduction Cardiovascular diseases are the leading cause of mortality in diabetic patients. Oxidative stress and mitochondrial dysfunction lead to diabetic cardiomyopathy (DCM) characterized by impaired cardiac structure and function. Hyperglycemia causes oxidative stress, which can lead to microvascular complications, macrovascular complications, and atherosclerosis. Peripheral tissues produce fibroblast growth factor 21 (FGF-21), which has anti-inflammatory properties, increases oxidation of fatty acids, and improves insulin sensitivity. Its increased levels are found in metabolic syndrome and type 2 diabetes mellitus and may also lead to coronary heart disease. Our study sought to measure the serum FGF-21 levels and their associations with lipid profile parameters and oxidative stress in patients with type 2 diabetes mellitus. Methodology One-hundred fifty (150) patients of both genders with type 2 diabetes mellitus were recruited along with 150 controls. Simple random sampling was done. After taking relevant history and physical examination, we drew venous blood samples of each patient and sent them to the institutional laboratory for analysis of fasting blood sugar (FBS) levels, glycated hemoglobin (HbA1C), lipid profile, and FGF-21 serum levels. Oxidative stress parameter malondialdehyde (MDA) was estimated and the total antioxidant status by ferric reducing antioxidant power assay (FRAP) was assessed. Patients were followed up after three months to record the glycemic index, and the values were recorded. We used SPSS Software 25.0 (SPSS, Inc., Chicago, USA) to analyze the data. For consideration of results to be statistically significant, a 𝑃 value of < 0.05 was selected. Results The levels of serum cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were increased in diabetics compared to controls and were statistically significant (p<0.05). High-density lipoprotein (HDL) cholesterol was lower in diabetic patients as compared to the controls (p<0.05). There was a statistically significant increase in the level of MDA in diabetics compared to controls (p˂0.005). Serum levels of total antioxidant status (FRAP) were decreased in diabetics in comparison with controls (p˂0.005). Serum FGF-21 level was statistically increased in diabetics compared to controls (p˂0.005). FGF-21 and MDA are positively correlated and FGF-21 and FRAP are negatively correlated. Serum FGF-21 is positively correlated with total cholesterol, triglycerides, serum LDL cholesterol, and HDL cholesterol. Conclusion Our study concludes that there is a significant correlation between fibroblast growth factor 21, oxidative stress, and abnormal lipid profile in type 2 diabetic patients. FGF-21 could be the target of certain medications used to treat metabolic disorders and obesity.

Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome.

INTRODUCTION: Foetal akinesia deformation sequence syndrome (FADS) is a genetically heterogeneous disorder characterised by the combination of foetal akinesia and developmental defects which may include pterygia (joint webbing). Traditionally multiple pterygium syndrome (MPS) has been divided into two forms: prenatally lethal (LMPS) and non-lethal Escobar type (EVMPS) types. Interestingly, FADS, LMPS and EVMPS may be allelic e.g. each of these phenotypes may result from mutations in the foetal acetylcholine receptor gamma subunit gene (CHRNG). Many cases of FADS and MPS do not have a mutation in a known FADS/MPS gene and we undertook molecular genetic studies to identify novel causes of these phenotypes. RESULTS: After mapping a novel locus for FADS/LMPS to chromosome 19, we identified a homozygous null mutation in the RYR1 gene in a consanguineous kindred with recurrent LMPS pregnancies. Resequencing of RYR1 in a cohort of 66 unrelated probands with FADS/LMPS/EVMPS (36 with FADS/LMPS and 30 with EVMPS) revealed two additional homozygous mutations (in frame deletions). The overall frequency of RYR1 mutations in probands with FADS/LMPS was 8.3%. CONCLUSIONS: Our findings report, for the first time, a homozygous RYR1 null mutation and expand the range of RYR1-related phenotypes to include early lethal FADS/LMPS. We suggest that RYR1 mutation analysis should be performed in cases of severe FADS/LMPS even in the absence of specific histopathological indicators of RYR1-related disease.