Lépidic adenocarcinoma of the Lung Mimicking multiple nodules and pulmonary cysts

Lepidic growth adenocarcinoma is defined as tumor cells proliferating along the surface of intact alveolar walls without stromal or vascular invasion pathologically (1).

Spontaneous pneumothorax, with or without pulmonary cysts, in patients with COVID-19 pneumonia

Introduction: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) affects mainly the lungs causing pneumonia and complications like acute respiratory distress syndrome. Pneumothorax is a rare manifestation of the disease. This report is a description of a series of patients with COVID-19 and spontaneous pneumothorax, some of them with associated pulmonary cysts. Methodology: Cases were collected retrospectively. We included clinical data from medical records and described radiologic findings. Patients that developed pneumothorax during mechanical ventilation were excluded. Results: Ten cases were included in this report, nine of them were male. The median age of our series was 62 years (IQR = 57-68). The median days since the onset of symptoms until the development of pneumothorax was 27 (IQR = 17-31), most cases developed after the second week of the diagnosis of pneumonia. Two cases required invasive mechanical ventilation, but pneumothorax occurred after ventilator weaning. Three cases showed subpleural pulmonary cysts. Conclusions: Cysts and pneumothorax are rare manifestations of SARS-CoV-2 pneumonia with mechanisms not completely understood. This report highlights the role of CT scan in diagnosis of COVID-19 complications.

A systematic review assessing the existence of pneumothorax-only variants of FLCN. Implications for lifelong surveillance of renal tumours

Individuals with Birt–Hogg–Dubé syndrome (BHDS) may develop fibrofolliculomas, pneumothorax and/or renal cell carcinoma (RCC). Currently, all patients with pathogenic FLCN variants are recommended to have renal surveillance. It has however been suggested that some FLCN variants only cause pneumothorax, which would make surveillance unnecessary in certain cases. This review assesses this possibility. We provide an up-to-date analysis of clinical and genetic features of BHDS. The PUBMED database was systematically searched to find all articles describing patients with pathogenic FLCN variants. The relevant clinical and genetic features of these patients were recorded and analysed. The prevalence of pneumothorax, pulmonary cysts, RCC and characteristic skin lesions in BHDS were 50.9% (n = 1038), 91.9% (n = 720), 22.5% (n = 929) and 47.9% (n = 989), respectively. There was a higher prevalence of pneumothoraces (p < 0.0001) but lower prevalence of dermatological findings (p < 0.0001) in patients from East Asia compared to North America or Europe. Of the 194 pathogenic FLCN variants, 76 could be defined as ‘pneumothorax-only’. Pneumothorax only pathogenic variants (POPVs) were distributed throughout the gene, and there were no statistical differences in variant type. The majority of POPVs (65/76) affected no more than three individuals. Individuals with ‘POPVs’ also tended to be younger (45 vs. 47 years, p < 0.05). Many apparent POPVs in the literature could result from variable expressivity, age-related penetrance and other confounding factors. We therefore recommend that all individuals found to carry a pathogenic FLCN variant be enroled in lifelong surveillance for RCC.

Novel folliculin gene mutations in Polish patients with Birt–Hogg–Dubé syndrome

Background Birt–Hogg–Dubé syndrome (BHDS) is a rare, autosomal dominant, inherited disease caused by mutations in the folliculin gene (FLCN). The disease is characterised by skin lesions (fibrofolliculomas, trichodiscomas, acrochordons), pulmonary cysts with pneumothoraces and renal tumours. We present the features of Polish patients with BHDS. Materials and methods The first case of BHDS in Poland was diagnosed in 2016. Since then, 15 cases from 10 families have been identified. Thirteen patients were confirmed via direct FLCN sequencing, and two according to their characteristic clinical and radiological presentations. Results BHDS was diagnosed in 15 cases (13 women and 2 men) from 10 families. The mean ages at the time of first pneumothorax and diagnosis were 38.4 ± 13.9 and 47.7 ± 13 years, respectively. Five patients (33%) were ex-smokers (2.1 ± 1.37 packyears), and 10 (67%) had never smoked cigarettes. Twelve patients (83%) had a history of recurrent symptomatic pneumothorax. Three patients had small, asymptomatic pneumothoraces, which were only detected upon computed tomography examination. All patients had multiple bilateral pulmonary cysts, distributed predominantly in the lower and middle, peripheral, and subpleural regions of the lungs. Generally, patients exhibited preserved lung function. Skin lesions were seen in four patients (27%), one patient had renal angiomyolipoma, and one had bilateral renal cancer. Different mutations of the FLCN gene were identified (mainly in exon 6), with two novel heterozygous variants: c.490delA p.(Arg164GlyTer13) and c.40delC p.(His14ThrsfTer41). Conclusions All analysed patients with BHDS presented with lung lesions and with less frequent skin and renal lesions than previously reported in other populations. In addition, more frequent mutations located in exon 6 were detected, and two novel FLCN gene mutations were identified.

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

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.

Prevalence of Birt-Hogg-Dubé Syndrome Determined Through Epidemiological Data on Spontaneous Pneumothorax and Bayes Theorem

Background: Birt-Hogg-Dubé syndrome (BHD) is a rare inherited disorder characterized by cutaneous fibrofolliculomas, multiple pulmonary cysts, recurrent spontaneous pneumothorax (SP), and renal tumors. More than 40 years after its description, the prevalence of BHD in the general population remains unknown. This study aimed at determining the prevalence of BHD by applying the Bayes theorem of conditional probability to epidemiological data on SP.Methods: We performed a meta-analysis of published data on: (1) the probability of having BHD among patients with apparent primary SP (4 studies), (2) the incidence rate of primary SP in the general population (9 studies), and (3) the probability of experiencing a SP in BHD (16 studies). Results were corrected for SP relapses, stratified by gender and year of study publication (before and after 2000), and computed with the Bayes equation.Results: The probability of having BHD among patients with apparent primary SP was 0.09 (95% confidence interval: 0.07, 0.11) or 9%. It was 0.20 (0.14, 0.27) in women and 0.05 (0.04, 0.07) in men. The incidence rate of primary SP in the general population was 8.69 (6.58, 11.46) per 100,000 person-years (p-y). It was 3.44 (2.36, 4.99) per 100,000 p-y in women and 13.96 (10.72, 18.18) per 100,000 p-y in men, and was about 2 times higher in studies published after 2000 than in those published before 2000. The probability of experiencing at least one SP among patients with BHD was 0.43 (0.31, 0.54) or 43%, without gender difference. By combining these data in the Bayes equation, we found a prevalence of BHD in the general population of 1.86 (1.16, 3.00) per million, with values of 1.86 (1.02, 3.39) per million in men, and 1.88 (0.97, 3.63) per million in women.Conclusion: The prevalence of BHD in the general population is about 2 cases per million, without difference between genders.

Abrogation of mesenchyme-specific TGF-β signaling results in lung malformation with prenatal pulmonary cysts in mice

The TGF-β signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-β signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-β signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-β signaling in regulating lung development and congenital lung diseases are not completely understood. Using a Tbx4 lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-β receptor 2 gene (Tgfbr2) is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal Tgfbr2 was deleted from embryonic day 13.5 to 15.5, resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1/2 may mediate these mesenchymal effects of TGF-β signaling through the GSK3β--β-catenin--Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-β signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-β signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions.

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

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.