A Novel De Novo Frameshift Pathogenic Variant in the FAM111B Resulting in Progressive Osseous Heteroplasia Phenotype.

INTRODUCTION: Progressive osseous heteroplasia (POH) is a rare, debilitating disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. While 60-70% of the POH patients have paternally inherited, inactivating pathogenic variants in GNAS, the remaining 30-40% have no known etiology. FAM111B pathogenic variants, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a very rare, autosomal-dominant disorder with high frequency of de novo missense pathogenic variants, which affects multiple tissues and organs, causing extensive fibrosis and muscle adiposis, though the exact mechanism is unknown. To our knowledge, there are no reports of FAM111B associated with POH. We describe the first case of POH phenotype associated with a novel de novo frameshift pathogenic variant in the FAM111B and present an analysis of the protein structure and function caused by this genomic disruption. CASE: A 15-year-old African-American male presented with generalized calcific nodules, progressive contractures, and muscle weakness leading to immobility, beginning at 6 years of age. Cutaneous examination showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs and computed tomography (CT) of the chest, abdomen, and pelvis showed extensive soft tissue and muscle heterotopic ossifications involving shoulders, axillae, trunk, abdomen, pelvis, upper and lower extremities, in a clumped, conglomerate distribution within muscle, subcutaneous fat, and in some areas extending to the skin. There was no pulmonary fibrosis on the chest CT. The clinical and radiographic findings were most consistent with POH. A trio-clinical exome sequencing revealed a de novo heterozygous likely pathogenic variant in the FAM111B (OMIM # 615584) (c.1462delT [p.Cys488Valfs*21]). The resulted frameshift change in exon 4 replaced C-terminal region with 21 alternative amino acids. Multiple, previously reported disease-associated variants appear to localize within the trypsin-like cysteine/serine peptidase domain in which this variant occurs, supporting the functional significance of this region, though none have been previously reported to be associated with POH phenotype. Our 3D protein modeling showed obliteration of predicted protein folding and structure, and elimination of the zinc-binding domain, likely severely affecting protein function. CONCLUSION: This is the first case of POH phenotype associated with a novel de novo pathogenic frameshift variant in FAM111B. Whether the frameshift change in FAM111B predicts POH remains unclear. Further evaluations are necessary to fully elucidate this finding and the potential role and mechanism by which the FAM111B variants contributes to POH phenotype.

Smoking & risk of advanced liver fibrosis among patients with primary biliary cholangitis: A systematic review & meta-analysis.

Background & objectives: Studies have suggested that smoking may accelerate the progression of fibrosis among patients with primary biliary cholangitis (PBC), although the data are limited. The current review was undertaken with the aim to comprehensively analyze this possible association by identifying all relevant studies and summarizing their results. Methods: A comprehensive literature review on MEDLINE and EMBASE databases was performed from inception through February 2019 to identify all relevant studies. Eligible studies included cross-sectional studies that recruited patients with PBC and collected data on the smoking status and presence or absence of advanced liver fibrosis for each participant. Odds ratios (OR) with 95 per cent confidence intervals (CI) was desirable for inclusion or sufficient raw data to calculate the same for this association. Adjusted point estimates from each study were extracted and combined together using the generic inverse variance method of DerSimonian and Laird. I2 statistic, which quantifies the proportion of total variation across studies was used to determine the between-study heterogeneity. Results: Three cross-sectional studies with 544 participants were included. The pooled analysis found a significantly increased risk of advanced liver fibrosis among patients with PBC who were ever-smokers compared to those who were nonsmokers with the pooled OR of 3.00 (95% CI, 1.18-7.65). Statistical heterogeneity was high with I2 of 89 per cent. Interpretation & conclusions: This meta-analysis found that smoking is associated with a significantly higher risk of advanced liver fibrosis among patients with PBC. Further prospective studies are still required to determine whether this association is causal.

Hereditary hemochromatosis and risk of joint replacement surgery: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Arthritis is a known manifestation of hereditary hemochromatosis. However, whether patients with hereditary hemochromatosis have an increased risk of having joint replacement surgery compared to the general population is still unknown. This meta-analysis was conducted to better characterize this risk. METHODS: A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through September 2019 to identify all cohort studies that compared prevalence or incidence of joint replacement surgery (hip, ankle, or knee) between patients with hereditary hemochromatosis and individuals without hereditary hemochromatosis. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: A total of five studies with 1 293 407 participants fulfilled the eligibility criteria and were included in the meta-analysis. Overall, the risk of having joint replacement surgery was significantly increased in patients with hereditary hemochromatosis compared to individuals without hereditary hemochromatosis with the pooled relative risk (RR) of 3.32 [95% confidence interval (CI), 1.60-6.86; I 88%]. Analysis by joint found a significantly increased risk of having hip and ankle replacement surgery among patients with hereditary hemochromatosis compared with the pooled RR of 2.62 (95% CI, 2.09-3.30; I 47%) and 8.94 (95% CI, 3.85-20.78; I 14%), respectively. The risk of having knee replacement surgery was also increased but was not statistically significant (pooled RR 1.57, 95% CI, 0.83-2.98; I 66%). CONCLUSIONS: A significantly increased risk of needed joint replacement surgery among patients with hereditary hemochromatosis compared to patients without hereditary hemochromatosis was demonstrated in this study. Further studies are required to determine whether this association is causal.

Incidence and Risk of Thyroid Dysfunction in Advanced or Metastatic Non-small Cell Lung Cancer Patients Treated with Pembrolizumab: A Meta-analysis.

Thyroid dysfunction is one of the major side effects associated with Pembrolizumab in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC). We performed a systematic review and meta-analysis of randomized clinical trials to determine its overall incidence. A literature search was conducted using the electronic database engines PubMed and Google Scholar from inception to March 2019. Eligible studies were prospective randomized clinical trials with advanced or metastatic NSCLC. The pooled incidence, risk ratio (RR), and 95% confidence interval (CI) of thyroid dysfunction were calculated using the random-effect model. Given the possibility of a between-study variance, we used the random-effect model rather than the fixed-effect model. A total of four studies, including 1603 patients, were selected for analysis. Among patients receiving Pembrolizumab, the overall incidence of all-grade thyroid dysfunction was 19.8% (95% CI: 16.6-23.3%). Pembrolizumab was associated with a significantly increased risk of thyroid dysfunction of all grades, with a relative risk of 3.9 (95% CI: 2.08-7.42%, p= 0.084) in comparison with the controls. Therefore, there is a significant increase in developing thyroid dysfunction in advanced or metastatic NSCLC patients treated with Pembrolizumab.

Association between Smoking and Risk of Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Studies have suggested that smokers may have a higher risk of primary biliary cholangitis (PBC) although the results have been inconsistent. This systematic review and meta-analysis aim to better characterize the risk of PBC among smokers by identifying all relevant studies and summarizing their results together. METHODS: A comprehensive literature review was conducted using Embase and Pubmed/MEDLINE databases from inception to September 2018 to identify all studies which compared the risk of PBC among current, ever and former smokers to non-smokers. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Nine case-control studies with 21,577 participants met the eligibility criteria and were included in the meta-analysis. The risk of PBC among ever smokers was significantly higher than non-smokers with the pooled odds ratio (OR) of 1.31 (95% CI, 1.03-1.67; I 2 89%). Subgroup analysis found that the risk was higher in both former smokers (pooled OR 1.36; 95% CI, 1.01-1.84; I 2 75%) and current smokers (pooled OR 1.18; 95% CI, 0.94-1.50; I 2 79%), although the latter did not reach statistical significance. Immunomodulatory and cytotoxic effect of cigarettes were the possible mechanisms behind this increased risk. CONCLUSIONS: A significantly increased risk of PBC among individuals who ever smoked was observed in this study, adding to the already long list of harmful health consequences of smoking.

Cigarette smoking and risk of celiac disease: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: A negative association between cigarette smoking and celiac disease has been observed but results were inconsistent across the published studies. A meta-analysis was conducted with the aim to identify all studies that investigated this association and to summarize the results of those studies. METHODS: A comprehensive literature review was conducted utilizing MEDLINE and Embase databases through March 2018 to identify all cohort studies and case-control studies that compared the risk of celiac disease among current and/or former smokers versus never-smokers. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: A total of seven studies with 307,924 participants fulfilled the eligibility criteria and were included in the meta-analysis. The pooled analysis found a significantly decreased risk of celiac disease among current smokers compared with never-smokers with the pooled odds ratio (OR) of 0.52 (95% confidence interval (CI), 0.32-0.84; I2 86%). However, the risk of celiac disease among former smokers was not significantly different from never-smokers with the pooled OR of 1.10 (95% CI, 0.76-1.60; I2 of 73%). CONCLUSIONS: A significantly decreased risk of celiac disease among current smokers compared with never-smokers was demonstrated in this meta-analysis.

Association Between Juxtapapillary Duodenal Diverticula and Risk of Choledocholithiasis: a Systematic Review and Meta-analysis.

BACKGROUND/OBJECTIVES: Studies have suggested that the presence of juxtapapillary duodenal diverticula (JDD) could be a predisposing factor for choledocholithiasis. This systematic review and meta-analysis was conducted with the aims to summarize all available evidence to better characterize the risk. METHODS: A literature search was performed using MEDLINE and EMBASE database from inception to January 2018. Cross-sectional studies that reported odd ratios (OR) comparing the risk of choledocholithiasis among individuals with JDD versus individuals without JDD were included. Pooled OR and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Of 527 retrieved articles, 11 studies met our eligibility criteria and were included in analysis. We found a significant association between the presence of JDD and choledocholithiasis with the pooled OR of 2.30 (95% CI, 1.84-2.86). The statistical heterogeneity was moderate with an I2 of 60%. CONCLUSIONS: A significantly increased risk of choledocholithiasis among individuals with JDD was observed in this study.

Association between smoking and risk of primary sclerosing cholangitis: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Studies have suggested that smokers may have a lower risk of primary sclerosing cholangitis (PSC) although the results have been inconsistent. This systematic review and meta-analysis was conducted to summarize all available data to better characterize this association. METHODS: A comprehensive literature review was conducted using Medline and Embase databases through January 2018 to identify all studies that compared the risk of PSC among current/former smokers versus nonsmokers. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Seven case-control studies with 2,307,393 participants met the eligibility criteria and were included in the meta-analysis. The risk of PSC among current smokers and former smokers was significantly lower than nonsmokers with the pooled odds ratio of 0.31 (95% CI, 0.18-0.53) and 0.52 (95% CI, 0.44-0.61), respectively. The risk remained significantly lower among current smokers and former smokers compared with nonsmokers even when only patients with PSC without inflammatory bowel disease were included. CONCLUSIONS: A significantly decreased risk of PSC among current and former smokers was demonstrated in this study.

Association between coffee consumption and risk of renal cell carcinoma: a meta-analysis.

BACKGROUND/OBJECTIVES: The risk of renal cell carcinoma (RCC) in individuals who regularly drink coffee is controversial. Several antioxidant compounds in coffee have been proposed to reduce the risk of RCC, while the findings from several studies raise concerns regarding a potential increased risk of RCC with coffee consumption. AIM: This meta-analysis aims to evaluate the association between coffee consumption and RCC. METHODS: A literature search was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception until December 2016. Studies that reported odd ratios or hazard ratios comparing the risk of RCC in individuals who consumed a significant amount of coffee (at least one cup of coffee per day) versus those who did not consume coffee were included. Pooled risk ratios (RR) and 95% confidence intervals (CI) were computed using a random-effect, generic inverse variance method. RESULTS: Twenty-two observational studies (16 case-control and 6 cohort studies) were included in our analysis to assess the association between RCC and coffee consumption. The pooled RR of RCC in individuals consuming coffee was 0.99 (95% CI, 0.89-1.11). Subgroup analyses stratified by gender showed pooled RRs of RCC of 1.15 (95% CI, 0.85-1.55) in females and 0.87 (95% CI, 0.72-1.04) in males. CONCLUSIONS: Our study demonstrates no significant association between coffee consumption and RCC. Thus, coffee consumption is likely not a risk factor for RCC. Whether coffee consumption has a potential role in reduced risk of RCC, particularly in men, requires further investigations.

Hepatitis C virus infection and risk of osteoporosis: A meta-analysis.

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection is one of the most common infections worldwide. Several epidemiologic studies have suggested that patients with HCV infection might be at an increased risk of osteoporosis. However, the data on this relationship remains inconclusive. This meta-analysis was conducted with the aim to summarize all available evidence. MATERIALS AND METHODS: A literature search was performed using MEDLINE and EMBASE databases from inception to June 2016. Studies that reported relative risks, odd ratios (OR), or hazard ratios comparing the risk of osteoporosis among HCV-infected patients versus those without HCV infection were included. Pooled OR and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Four studies met our eligibility criteria and were included in the analysis. We found a higher risk of osteoporosis among patients with chronic HCV with OR of 1.65 (95% CI: 0.98-2.77). Sensitivity analysis including only studies with higher quality yielded a higher OR, and the result was statistically significant (OR: 2.47; 95% CI: 1.03-5.93). CONCLUSIONS: Our study demonstrated a higher risk of osteoporosis among HCV-infected patients. Further studies are required to clarify how this risk should be addressed in clinical practice.

Vincristine-induced polyneuropathy in a child with stage I Wilms' tumour presenting with unilateral abducens nerve palsy.

A 4-year-old boy presented with right esotropia while receiving vincristine and dactinomycin for stage I Wilms' tumour according to the National Wilms Tumour Study-5 protocol. On examination, he had isolated limitation of his right lateral gaze. CT of the brain and cerebrospinal fluid examination were normal. A nerve conduction velocity study which was performed on the peripheral nerves revealed predominant motor polyneuropathy compatible with axonal loss involving the upper limbs. The patient had received a cumulative vincristine dose of 17 mg/m(2) before developing esotropia. Vincristine-induced abducens nerve mononeuropathy and subclinical motor polyneuropathy was suspected. Unilateral esotropia markedly improved after the discontinuation of vincristine and a short course of oral pyridoxine treatment.