scholarly journals A Novel FLCN Intragenic Deletion Identified by NGS in a BHDS Family and Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Minghui Cai ◽  
Xinxin Zhang ◽  
Lizhen Fan ◽  
Shuwen Cheng ◽  
Abdukahar Kiram ◽  
...  
Keyword(s):  
Spontaneous Pneumothorax ◽  
Relevant Literature ◽  
Skin Lesions ◽  
Targeted Next Generation Sequencing ◽  
Advantages And Disadvantages ◽  
Intragenic Deletion ◽  
Pulmonary Cysts ◽  
Targeted Ngs ◽  
Atypical Manifestations ◽  
Intragenic Deletions

Birt–Hogg–Dubé syndrome (BHDS, MIM #135150), caused by germline mutations of FLCN gene, is a rare autosomal dominant inherited disorder characterized by skin fibrofolliculomas, renal cancer, pulmonary cysts and spontaneous pneumothorax. The syndrome is considered to be under-diagnosed due to variable and atypical manifestations. Herein we present a BHDS family. Targeted next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) revealed a novel FLCN intragenic deletion spanning exons 10-14 in four members including the proband with pulmonary cysts and spontaneous pneumothorax, one member with suspicious skin lesions and a few pulmonary cysts, as well as two asymptomatic family members. In addition, a linkage analysis further demonstrated one member with pulmonary bullae to be a BHDS-ruled-out case, whose bullae presented more likely as an aspect of paraseptal emphysema. Furthermore, the targeted NGS and MLPA data including our previous and present findings were reviewed and analyzed to compare the advantages and disadvantages of the two methods, and a brief review of the relevant literature is included. Considering the capability of the targeted NGS method to detect large intragenic deletions as well as determining deletion junctions, and the occasional false positives of MLPA, we highly recommend targeted NGS to be used for clinical molecular diagnosis in suspected BHDS patients.

scholarly journals Birt–Hogg–Dubé syndrome in Chinese patients: a literature review of 120 families

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Xiaowen Hu ◽  
Guofeng Zhang ◽  
Xianmeng Chen ◽  
Kai-Feng Xu
Keyword(s):  
Spontaneous Pneumothorax ◽  
Delayed Diagnosis ◽  
Clinical Manifestations ◽  
Lower Lobe ◽  
Skin Lesions ◽  
Jiangsu Province ◽  
Chinese Patients ◽  
Renal Tumors ◽  
Pulmonary Cysts ◽  
Exon 11

Abstract Objective To clarify the epidemiological and clinical features of Birt–Hogg–Dubé syndrome (BHDS) in Chinese patients. Methods We identified reports on Chinese patients with BHDS by searching the China Academic Journals Database, Wanfang Chinese Database, and PubMed databases, either in Chinese or English languages published from January 1, 2008 to December 31, 2020. Studies without sufficient clinical data were excluded and cases under 18 years old were excluded. Results Twenty papers were included and comprised 120 families with 221 cases. Most families with BHDS were reported from institutions in Beijing (66.7%) and Jiangsu Province (15.8%); 80.8% of cases were reported within the past five years. The average duration from clinical presentation to diagnosis was 9.6 years. The average age was 47.0 ± 13.9 years (range, 18–84 years) and the ratio of male to female was 1:1.6. The most common manifestations of BHDS were multiple pulmonary cysts (92.4%), spontaneous pneumothorax (71.0%), skin lesions (18.1%) and renal tumors (3.6%). Pulmonary cysts were predominantly distributed in the lower lobe on chest CT imaging. Family history of spontaneous pneumothorax was identified in 84.7% of the families and average number of pneumothoraxes was 1.8 (range, 1–6). The FLCN gene mutation c.1285dupC/delC in exon 11 was the most frequent mutation observed (17.4% of patients). The recurrence rate of pneumothorax after conservative treatment (including tube thoracostomy) was 29/41 (71%) while the pneumothorax recurred after surgical treatment (pulmonary bullectomy or pleurodesis) in only 4/37 (11%). Conclusions Although BHDS has been increasingly reported in the recent years, only minority of families were reported from institutions outside of Beijing and Jiangsu Province. The dominant clinical manifestations were pulmonary cysts associated with recurrent pneumothorax, while skin lesions and renal tumors were less commonly reported. Delayed diagnosis along with suboptimal management appear to represent critical challenges for Chinese patients with BHDS.

Birt-Hogg-Dubé Syndrome in Chinese Patients: A Literature Review of 120 Families

2021 ◽  
Author(s):  
Guofeng Zhang ◽  
Xianmeng Chen ◽  
Kaifeng Xu ◽  
Xiaowen Hu
Keyword(s):  
Spontaneous Pneumothorax ◽  
Delayed Diagnosis ◽  
Clinical Manifestations ◽  
Lower Lobe ◽  
Skin Lesions ◽  
Jiangsu Province ◽  
Chinese Patients ◽  
Renal Tumors ◽  
Pulmonary Cysts ◽  
Exon 11

Abstract ObjectiveTo clarify the epidemiological and clinical features of Birt-Hogg-Dubé syndrome (BHDS) in Chinese patients. MethodsWe identified reports on Chinese patients with BHDS by searching the China Academic Journals Database, Wanfang Chinese Database, and PubMed databases, either in Chinese or English languages published from January 1, 2006 to December 31, 2020. Studies without sufficient clinical data were excluded and cases under 18 years old were excluded. ResultsTwenty papers were included and comprised 120 families with 221 cases. Most families with BHDS were reported from institutions in Beijing (66.7%) and Jiangsu Province (15.8%); 80.8% of cases were reported within the past five years. The average duration from clinical presentation to diagnosis was 9.6 years. The average age was 47.0±13.9 years (range, 18-84 years) and the ratio of male to female was 1:1.6. The most common manifestations of BHDS were multiple pulmonary cysts (92.4%), spontaneous pneumothorax (71.0%), skin lesions (18.1%) and renal tumors (3.6%). Pulmonary cysts were predominantly distributed in the lower lobe on chest CT imaging. Family history of spontaneous pneumothorax was identified in 84.7% of the families and average number of pneumothoraxes was 1.8 (range, 1-6). The FLCN gene mutation c.1285dupC/delC in exon 11 was the most frequent mutation observed (17.4% of patients). The recurrence rate of pneumothorax after conservative treatment (including tube thoracostomy) was 29/41 (71%) while the pneumothorax recurred after surgical treatment (pulmonary bullectomy or pleurodesis) in only 4/37 (11%).ConclusionsAlthough BHDS has been increasingly reported in the recent years, only minority of families were reported from institutions outside of Beijing and Jiangsu Province. The dominant clinical manifestations were pulmonary cysts associated with recurrent pneumothorax, while skin lesions and renal tumors were less commonly reported. Delayed diagnosis along with suboptimal management appear to represent critical challenges for Chinese patients with BHDS.

scholarly journals Birt-Hogg-Dubé syndrome presenting with spontaneous pneumothorax and extensive pulmonary cysts in the absence of skin lesions or renal pathology

2019 ◽  
Vol 12 (9) ◽  
pp. e231039
Author(s):  
Kartik Kumar ◽  
Clare Ross
Keyword(s):  
Spontaneous Pneumothorax ◽  
Autosomal Dominant ◽  
Skin Lesions ◽  
Lung Cysts ◽  
Cystic Lung ◽  
Increased Risk ◽  
Renal Tumours ◽  
Pulmonary Cysts ◽  
Dominant Condition ◽  
Bhd Syndrome

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition which classically manifests with skin lesions such as fibrofolliculomas, pulmonary cysts that predispose to spontaneous pneumothorax and an increased risk of developing renal cell carcinoma. We describe the case of a patient who presented with a spontaneous pneumothorax on a background of multiple lung cysts, in the absence of cutaneous fibrofolliculomas and renal tumours. A germline mutation in the folliculin FLCN gene was subsequently identified, confirming BHD syndrome. Our case highlights the importance of considering a broad differential diagnosis for the cause of a spontaneous pneumothorax in the presence of unexplained cystic lung disease and emphasises the value of maintaining a high index of clinical suspicion for inherited causes of pneumothoraces.

scholarly journals LGG-28. NOVEL BRAF INTRAGENIC DELETION IN A GLIOMA: A CASE REPORT OF A PEDIATRIC PATIENT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii371-iii372
Author(s):  
Valerie Cruz Flores ◽  
Maxine Sutcliffe ◽  
Thomas Geller ◽  
Ignacio Gonzalez Gomez ◽  
Stephanie Smith ◽  
...  
Keyword(s):  
Pediatric Patient ◽  
Pilocytic Astrocytoma ◽  
Pediatric Population ◽  
Binding Pocket ◽  
Genetic Alterations ◽  
Low Grade ◽  
Braf Gene ◽  
Intragenic Deletion ◽  
Whole Genome Microarray ◽  
Intragenic Deletions

Abstract BACKGROUND Numerous variant BRAF genetic alterations have been associated with malignancies. BRAF activating fusions/mutations are frequently present in low grade gliomas. BRAF intragenic deletions have been reported in melanoma, but have not previously been reported in gliomas. OBJECTIVE To report a BRAF intragenic deletion in a pediatric patient with recurrent low-grade glioma. RESULTS A 3-year-old female underwent a complete resection of a posterior fossa pilocytic astrocytoma. She had recurrences at age 4, and then at age 9; pathology was consistent with pilocytic astrocytoma. Microarray analysis on sample from the first recurrence showed one region of loss encompassing 86 Kbp within the BRAF gene. The deletion breakpoints are within intron 1 and 9, resulting in loss of exons 2 through 9, inclusive. This has been previously described melanoma, but appears to be a novel finding in glioma. It is hypothesized that, since the loss retains the kinase and ATP binding pocket domains but deletes the N-terminal conserved region 1 and 2 (CR1, CR2) of the BRAF gene, it is likely functionally similar to the loss and activation resulting from the more usually described KIAA1549 and BRAF gene fusion. CONCLUSION This is the first BRAF intragenic deletion involving exons 2–9 reported in a glioma. Although 86kbp is small using whole genome microarray technology, it is large using sequencing strategies, and a targeted sequencing approach to investigate the BRAF gene would not readily identify this deletion. It is speculated that the deletion may be under ascertained in the pediatric population.

The “Surge Phenomenon” of Macro Economy in Developing Countries from the Perspective of Tobacco Economy

2021 ◽  
Vol 7 (4) ◽  
pp. 663-673
Author(s):  
Lulu Liu
Keyword(s):  
Developing Countries ◽  
Tobacco Industry ◽  
Investment Decision ◽  
Relevant Literature ◽  
Economic Benefits ◽  
Social Costs ◽  
Advantages And Disadvantages ◽  
The Social ◽  
The Government ◽  
The Impact

Objectives: Starting from the tobacco economy, this paper studies the “surge phenomenon” of macro-economy in developing countries. Methods: This paper studies the impact of tobacco industry on Anhui economy by using the relevant theories of industrial economics, econometrics and regulatory economics, combined with the actual situation of tobacco industry. Based on the analysis of the overall development of tobacco industry, this paper empirically analyzes the relationship between tobacco industry and Anhui economic growth. This paper combs the relevant literature of the existing research results of this theory. Combined with the special fact that government investment accounts for a large proportion in China’s current economic construction, this paper redefines the hypothesis of the investor in the theory of principles. On this basis, the expected equilibrium results of enterprise investment decision-making under government led and market led modes are compared and analyzed by using incomplete information static game model. Results: When the output value of tobacco industry increases by 1%, it will drive the GDP to increase by 0.373%. Secondly, by comparing the economic benefits of tobacco with the social costs of tobacco, it is found that with the economic development, the social costs caused by tobacco increase year by year, but the economic benefits are slightly greater than the social costs. The difference between the two is also increasing year by year. Conclusion: In the context of tobacco control, we should fully consider the advantages and disadvantages of developing the tobacco industry. Under the excessive intervention of the government, the manifestation of the surge phenomenon is more intense, and the final consequence of overcapacity is more serious than that under the market-oriented mode..

scholarly journals The ICR96 exon CNV validation series: a resource for orthogonal assessment of exon CNV calling in NGS data

2017 ◽  
Vol 2 ◽  
pp. 35 ◽  
Author(s):  
Shazia Mahamdallie ◽  
Elise Ruark ◽  
Shawn Yost ◽  
Emma Ramsay ◽  
Imran Uddin ◽  
...  
Keyword(s):  
Sequencing Data ◽  
Targeted Next Generation Sequencing ◽  
Negative Results ◽  
Targeted Ngs ◽  
Predisposition Genes ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
Validation Series ◽  
Generation Sequencing ◽  
Dependent Probe

Detection of deletions and duplications of whole exons (exon CNVs) is a key requirement of genetic testing. Accurate detection of this variant type has proved very challenging in targeted next-generation sequencing (NGS) data, particularly if only a single exon is involved. Many different NGS exon CNV calling methods have been developed over the last five years. Such methods are usually evaluated using simulated and/or in-house data due to a lack of publicly-available datasets with orthogonally generated results. This hinders tool comparisons, transparency and reproducibility. To provide a community resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM or PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs, the most difficult type of exon CNV to detect. The FASTQ files for the ICR96 exon CNV validation series can be accessed through the European-Genome phenome Archive (EGA) under the accession number EGAS00001002428.

scholarly journals Opportunities and Questions: A Short Report on Rubric Assessments in Asia and the Middle East

2019 ◽  
Author(s):  
Ronnie Goodwin
Keyword(s):  
Middle East ◽  
Assessment Tool ◽  
Relevant Literature ◽  
Alternative Methods ◽  
Learning Theories ◽  
Short Report ◽  
Rating Systems ◽  
Self Assessment ◽  
Advantages And Disadvantages ◽  
The Impact

This qualitative short report considers the viability of the use of rubrics or alternative methods to assess writing in Asia and the Middle East. The background of learning theories, assessment types, and self-assessment literature provides a foundation for further discussion of the appropriate use of rubrics, including the prioritization of criterion, the quality of scoring, the impact of organizational features on scoring, the influence of bias, and the best application of rubric assessment. Relevant points for further study are identified, such as differentiation in research between generalized analytical rating systems and rubric assessment with specific, empirical criterion. The contradictory research regarding the advantages and disadvantages of rubric assessment in comparison with holistic assessment are of particular and crucial interest for global pedagogy. Many of the reviewed Western articles excluded Asian perspectives- except for China- and thus present a limited understanding of social and educational compatibility with new assessments and rubric assessments in particular. The discussion identifies patterns and points of contention and seeks to explore viewpoints rather than limit the scope of inquiry and consideration thus noting that relevant literature suggests that with appropriate teacher training, teachers may appropriately use rubrics as a formative assessment tool for writing in Asia and the Middle East.

scholarly journals Pleurodesis methods in the surgical treatment of primary spontaneous pneumothorax

2021 ◽  
pp. 77-81
Keyword(s):  
Surgical Treatment ◽  
Recurrence Rate ◽  
Spontaneous Pneumothorax ◽  
Thoracoscopic Surgery ◽  
Wedge Resection ◽  
Primary Spontaneous Pneumothorax ◽  
High Recurrence Rate ◽  
Parietal Pleura ◽  
Advantages And Disadvantages ◽  
Video Assisted Thoracoscopic Surgery

Pneumothorax is the collection of air in the pleural space. Pneumothorax can be spontaneous, traumatic or iatrogenic. Primary spontaneous pneumothorax mostly occurs in healthy individuals without an apparent cause, probably due to the rupture of subpleural emphysematous bullae located on the apex of the lung. It usually occurs in tall and healthy males younger than 40 years old. Primary spontaneous pneumothorax has a recurrence rate of 20-30% after the first attack, 50% after the second attack, and 80% after the third attack. Surgery is presented as a treatment option to reduce the high recurrence rate after the second attack. It has been reported that recurrence is between 10 and 20% in patients who undergo bullectomy or wedge resection with endoscopic steps alone. Therefore, various pleural pleurodesis methods are applied in addition to bulla resection in order to reduce the recurrence rate after surgery. In mechanical pleurodesis, adhesion between visceral and parietal pleura is achieved by mechanical abrasion of the parietal pleura or by total or partial removal of the parietal pleura. In chemical pleurodesis, the visceral pleura is adhered to the parietal pleura by creating irritation in the pleura with chemical agents. In cases where pleurodesis was added, the recurrence rate was reported to be between 1.7 and 2.8%. Whether the pleurectomy, pleural mechanical or chemical abrasion methods performed with video-assisted thoracoscopic surgery is superior for preventing recurrence is still a matter of debate. In this article, we aimed to discuss the advantages and disadvantages of pleurodesis methods in the surgical treatment of primary spontaneous pneumothorax in the light of the literature.

scholarly journals Targeted Next-Generation Sequencing of Cancer-Related Genes in a Norwegian Patient Cohort With Head and Neck Squamous Cell Carcinoma Reveals Novel Actionable Mutations and Correlations With Pathological Parameters

2021 ◽  
Vol 11 ◽  
Author(s):  
Harsh N. Dongre ◽  
Hilde Haave ◽  
Siren Fromreide ◽  
Fredrik A. Erland ◽  
Svein Erik Emblem Moe ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Head And Neck ◽  
Squamous Cell ◽  
Ffpe Tissue ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Mutational Burden ◽  
Custom Made ◽  
Targeted Ngs ◽  
Generation Sequencing

BackgroundTargeted next-generation sequencing (NGS) is increasingly applied in clinical oncology to advance personalized treatment. Despite success in many other tumour types, use of targeted NGS panels for assisting diagnosis and treatment of head and neck squamous cell carcinomas (HNSCC) is still limited.AimThe focus of this study was to establish a robust NGS panel targeting most frequent cancer mutations in long-term preserved formalin-fixed paraffin-embedded (FFPE) tissue samples of HNSCC from routine diagnostics.Materials and MethodsTumour DNA obtained from archival FFPE tissue blocks of HNSCC patients treated at Haukeland University Hospital between 2003-2016 (n=111) was subjected to mutational analysis using a custom made AmpliSeq Library PLUS panel targeting 31 genes (Illumina). Associations between mutational burden and clinical and pathological parameters were investigated. Mutation and corresponding clinicopathological data from HNSCC were extracted for selected genes from the Cancer Genome Atlas (TCGA) and used for Chi-square and Kaplan-Meier analysis.ResultsThe threshold for sufficient number of reads was attained in 104 (93.7%) cases. Although the specific number of PCR amplified reads detected decreased, the number of NGS-annotated mutations did not significantly change with increased tissue preservation time. In HPV-negative carcinomas, mutations were detected mainly in TP53 (73.3%), FAT1 (26.7%) and FLG (16.7%) whereas in HPV-positive, the common mutations were in FLG (24.3%) FAT1 (17%) and FGFR3 (14.6%) genes. Other less common pathogenic mutations, including well reported SNPs were reproducibly identified. Presence of at least one cancer-specific mutations was found to be positively associated with an extensive desmoplastic stroma (p=0.019), and an aggressive type of invasive front (p=0.035), and negatively associated with the degree of differentiation (p=0.041). Analysis of TCGA data corroborated the association between cancer-specific mutations and tumour differentiation and survival analysis showed that tumours with at least one mutation had shorter disease-free and overall survival (p=0.005).ConclusionsA custom made targeted NGS panel could reliably detect several specific mutations in archival samples of HNSCCs preserved up to 17 years. Using this method novel associations between mutational burden and clinical and pathological parameters were detected and actionable mutations in HPV-positive HNSCC were discovered.

A 48-Year-Old Woman With Skin Lesions, Renal Masses, and Spontaneous Pneumothorax

CHEST Journal ◽  
2007 ◽  
Vol 131 (2) ◽  
pp. 624-627 ◽  
Author(s):  
Ravi Kalhan ◽  
Anjana V. Yeldandi ◽  
Manu Jain
Keyword(s):  
Spontaneous Pneumothorax ◽  
Skin Lesions ◽  
Renal Masses
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