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Abstract A genetic influence on spontaneous pneumothoraces—those occurring without a traumatic or iatrogenic cause—is supported by several lines of evidence: 1) pneumothorax can cluster in families (i.e., familial spontaneous pneumothorax), 2) mutations in the FLCN gene have been found in both familial and sporadic cases, and 3) pneumothorax is a known complication of several genetic syndromes. Herein, we review known genetic contributions to both sporadic and familial pneumothorax. We summarize the pneumothorax-associated genetic syndromes, including Birt-Hogg-Dubé syndrome, Marfan syndrome, vascular (type IV) Ehlers-Danlos syndrome, alpha-1 antitrypsin deficiency, tuberous sclerosis complex/lymphangioleiomyomatosis, Loeys-Dietz syndrome, cystic fibrosis, homocystinuria, and cutis laxa, among others. At times, pneumothorax is their herald manifestation. These syndromes have serious potential extrapulmonary complications (e.g., malignant renal tumors in Birt-Hogg-Dubé syndrome), and surveillance and/or treatment is available for most disorders; thus, establishing a diagnosis is critical. To facilitate this, we provide an algorithm to guide the clinician in discerning which cases of spontaneous pneumothorax may have a genetic or familial contribution, which cases warrant genetic testing, and which cases should prompt an evaluation by a geneticist.

Smurf1 mediates lysosomal biogenesis upon endomembrane damage by interacting with lysosomal injury sensor Gal3 and phosphatase CaN to form Gal3‐CaN‐Smurf1 complex, which is critical for TFEB dephosphorylation. However, whether Smurf1 plays a role in the inhibition of mTOR‐mediated TFEB phosphorylation is still unclear. TFEB phosphorylation by mTORC1 is strictly dependent on RagC/D GTPase activating protein FLCN. Here, we found that Smurf1 promotes the dissociation of RagC from TFEB upon lysosomal damage, selectively impairing TFEB phosphorylation. These findings suggest that the lysosomal damage‐induced Gal3‐CaN‐Smurf1 complex sequesters FLCN‐FNIPs to facilitate TFEB activation. This disruption of FLCN GAP function toward RagC/D impairs TFEB's lysosomal localization and phosphorylation. Notably, FLCNK462R and/or FNIP2K466R mutations reduce their binding affinity with the Gal3‐CaN‐Smurf1 complex, suggesting Smurf1‐mediated poly‐ubiquitylation of FLCNK462 and FNIP2K466 plays a role for pentamer formation. Indeed, sequestration of FLCN‐FNIPs stabilizes the Gal3‐CaN‐Smurf1 complex, wherein Smurf1 directly binds and ubiquitinates TFEB. This facilitates TFEB's dephosphorylation and activation. These findings indicate that Gal3‐CaN‐Smurf1 complex interconnects with the FLCN‐FNIPs to orchestrate TFEB localization and activity in response to lysosomal damage stress. Understanding Smurf1's regulation in the mTOR‐TFEB axis, which balances tumor growth and stress‐induced cell homeostasis, may provide novel therapeutic targets for tumor progression and drug resistance. The schematic diagram illustrates the role of the recruitment of Gal3‐CaN‐Smurf1 complex in maintaining lysosomal membrane homeostasis upon damage. On the one hand, the Gal3‐CaN‐Smurf1 complex sequesters FLCN‐FNIPs to block the activation of RagC, where the active form RagC‐GDP is responsible for TFEB phosphorylation. On the other hand, FLCN‐FNIPs stabilizes Gal3‐CaN‐Smurf1 complex for the recruitment and CaN‐mediated dephosphorylation of TFEB.

Purpose Autosomal dominant polycystic kidney disease (ADPKD) represents the most common hereditary nephropathy. Despite growing evidence for genetic heterogeneity, ADPKD diagnosis is still primarily based upon clinical imaging criteria established before discovery of additional PKD genes. This study aimed at assessing the diagnostic value of genetic verification in clinical ADPKD. Methods In this prospective, diagnostic trial, 100 families with clinically diagnosed ADPKD were analyzed by PKD gene panel and multiplex ligation-dependent probe amplification (MLPA); exome sequencing (ES) was performed in panel/MLPA-negative families. Results Diagnostic PKD1/2 variants were identified in 81 families (81%), 70 of which in PKD1 and 11 in PKD2 . PKD1 variants of unknown significance were detected in another 9 families (9%). Renal survival was significantly worse upon PKD1 truncation versus nontruncation and PKD2 alteration. Ten percent of the cohort were PKD1 / 2- negative, revealing alternative genetic diagnoses such as autosomal recessive PKD, Birt–Hogg–Dubé syndrome, and ALG9 -associated PKD. In addition, among unsolved cases, ES yielded potential novel PKD candidates. Conclusion By illustrating vast genetic heterogeneity, this study demonstrates the value of genetic testing in a real-world PKD cohort by diagnostic verification, falsification, and disease prediction. In the era of specific treatment for fast progressive ADPKD, genetic confirmation should form the basis of personalized patient care.

Background: Birt–Hogg–Dubé syndrome (BHD) was an autosomal dominant disorder caused by a mutation in the folliculin ( FLCN ) gene and characterized by benign cutaneous fibrofolliculomas in the head and neck, pulmonary cysts, spontaneous pneumothorax, and combined renal tumors. Methods: This study reported a familial case presenting multiple pulmonary bullae, recurrent spontaneous pneumothorax, diffuse cystic lesions in both lungs, and renal cysts. To further clarify the diagnosis, next‐generation sequencing (NGS) was performed in conjunction with the clinical diagnostic criteria for Birt–Hogg–Dubé. The eukaryotic recombinant expression vectors of pEGFP‐C1‐ FLCN and knock‐in FLCN mutation by CRISPR/Cas9 were conducted in 293 T and BEAS‐2B cell lines. The mRNA and protein expression of the FLCN mutation were verified by fluorescence quantitative PCR and Western blot assay. Nonsense‐mediated mRNA decay (NMD) assays and immunohistochemical assays were conducted to elucidate the pathogenicity of the mutation and explore potential mechanisms. Results: A unique, novel, unspecified significance FLCN mutation NM_144997.7: c.21_22del (p. Cys8 Profs  ∗ 28) in Exon 4 was detected in both patients. The results demonstrated that the newly identified FLCN frameshift mutation significantly decreased FLCN mRNA and protein expression. The NMD complex recognized and degraded mRNAs containing a premature termination codon (PTC) in the open reading frame of the FLCN frameshift mutation, resulting in haploinsufficiency and ultimately contributing to the manifestation of BHD. Protein expression on the AMP‐activated protein kinase (AMPK), Wnt/ β ‐catenin, and mammalian target of rapamycin (mTOR) signaling pathways by immunohistochemistry indicated that FLCN frameshift mutations were responsible for BHD through the activation of AMPK, Wnt/ β ‐catenin, and mTOR signaling pathways. Conclusion: The study demonstrated that a novel FLCN frameshift mutation was responsible for the pathogenesis of BHD and preliminarily demonstrated that FLCN causes BHD through the AMPK, Wnt/ β ‐catenin, and mTOR signaling pathways.

Background Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. Results Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. Conclusions Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

Folliculin, encoded by gene, plays a role in the mTORC1 autophagy cascade and its alterations are responsible for the Birt-Hogg-Dubé (BHD) syndrome, characterized by follicle hamartomas, kidney tumors and pneumothorax. We report a 74-years-old woman diagnosed with dementia and carrying a alteration in absence of any sign of BHD. She also carried an alteration of gene, which is also implicated in the regulation of mTORC1. The variant could have prevented the development of a -related oncological phenotype. Conversely, our patient presented with dementia that, to date, has yet to be documented in BHD. Folliculin belongs to the DENN family proteins, which includes C9orf72 whose alteration has been associated to neurodegeneration. The folliculin perturbation could affect the C9orf72 activity and our patient could represent the first human model of a relationship between FLCN and C9orf72 across the path of autophagy.

Background Although an increasing number of patients with Birt-Hogg-Dubé syndrome (BHD) are being recognized in China, clinical and genetic characteristics are not well-defined. In addition, revised diagnostic criteria for the Chinese population was proposed in 2023, we aimed to explore their utility in clinical practice at a rare lung disease center. Methods We retrospectively analyzed the data of 100 consecutive patients with BHD diagnosed according to the revised Chinese BHD criteria, encountered at the First Affiliated Hospital of University of Science and Technology of China from Jan 2017 to June 2023. Results There were 100 patients (including 63 females) from 65 unrelated families in Eastern China, mostly Anhui Province. The common manifestations were pulmonary cysts (99%), pneumothorax (60%), and skin lesions (77%). Renal cancer and renal angiomyolipoma were detected in 5 patients each. 37% of patients had no family history of BHD. In total, 25 FLCN germline mutations were detected, including 6 novel mutations. In addition to hotspot mutation c.1285delC/dupC (17%), the most common mutations were c.1015 C > T (16%), c.1579_1580insA (14%), and exons 1–3 deletion (11%) in FLCN . Higher risk of pneumothorax was associated with exons 1–3 deletion mutation and c.1177-5_1177-3de1CTC compared to the hotspot mutation c.1285dupC (91% [95% CI: 0.31, 46.82, p  = 0.015] and 67% [95% CI: 0.35, 71.9, p  = 0.302] vs. 30%, respectively). The average delay in diagnosis was 7.6 years after initial symptoms. Chinese diagnostic criteria were mostly consistent with typical pulmonary presentations with supportive genetic evidence. Conclusion In the Eastern Chinese region, patients with BHD present most commonly with pulmonary cysts associated with pneumothorax and skin lesions. However, low incidence of renal cancer along with unexpected renal angiomyolipoma was observed. Genotypic spectrum differed from that reported from other global regions, and genotype association of pneumothorax warrants further research. The revised Chinese criteria for BHD seem more appropriate in diagnosing BHD in Chinese patients.

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.

Background Birt–Hogg–Dubé syndrome (BHDS) is a rare inherited disorder defined by skin lesions, pulmonary cysts, spontaneous pneumothorax, and renal neoplasia. Mutations in the FLCN gene are known causes, and identifying specific variants in different populations is essential for elucidating genotype-phenotype correlations. Methods We investigated a Chinese family with suspected BHDS. The proband was admitted to the Affiliated Cangnan Hospital of Wenzhou Medical University in October 2023. Comprehensive clinical evaluations and imaging studies were performed. Peripheral blood samples were collected from the proband and available family members after obtaining informed consent. Whole-exome sequencing (WES) was conducted to identify potential variants in the FLCN gene. Candidate variants were subsequently validated by Sanger sequencing and analyzed for co-segregation within the family. Pathogenicity was assessed in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. To illustrate the structural impact of the variant, a three-dimensional model of the folliculin protein was generated using SWISS-MODEL and visualized with PyMOL. Results The proband exhibited bilateral pulmonary cysts, a small left-sided pneumothorax, a left renal mass, and possible cutaneous manifestations. Family evaluation identified pulmonary cysts in multiple children, with pneumothorax in some and a history of lobectomy in two. Genetic testing revealed a heterozygous FLCN nonsense variant, NM_144997.7:c.1222 C > T (p.Gln408Ter), in the proband and one son, while her husband and asymptomatic daughter were noncarriers. This variant meets ACMG criteria for pathogenicity. Structural modeling demonstrated that the premature stop codon truncates folliculin at residue 408, eliminating most of the C-terminal domain and severely compromising protein integrity. Although this variant is listed in ClinVar (RCV001953597) as pathogenic, detailed phenotypic documentation has been limited, and it has not been previously described in Chinese BHDS patients. Conclusions We describe, to our knowledge, the first report of the FLCN NM_144997.7:c.1222 C > T (p.Gln408Ter) variant in a Chinese BHDS family and characterize its associated clinical phenotype. These findings extend the known FLCN variant spectrum, enhance population-specific genotype–phenotype understanding, and offer meaningful evidence for clinical diagnosis and genetic counseling.