Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax

Xing, H. Rosie; Liu, Yanguo; Jiang, Guanchao; Xiao, Li; Hou, Yingyong; Yang, Fan; Wang, Jun

doi:10.21037/jtd.2017.06.69

Cited by 11 publications

(10 citation statements)

References 28 publications

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“…In the affected family members, there were similar numbers of men and women, and the median age of onset of pneumothorax was 42.5 years, which was consistent with the results from two recent studies of the large families with BHD syndrome. Skolnik et al [21] reported that the mean age at diagnosis was 42 years, and Xing et al [9] suggested that the median age at initial onset was 41.5 years from another large Chinese family with BHD syndrome. Smoking history is not the risk factor for the disease, which was also indicated in this family.…”

Section: Discussionmentioning

confidence: 99%

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Recurrent primary spontaneous pneumothorax in a large Chinese family

Zheng

Gao

et al. 2019

Chinese Medical Journal

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Background:Primary spontaneous pneumothorax (PSP) is a common manifestation of Birt-Hogg-Dubé (BHD) syndrome, which is an autosomal dominant disorder caused by mutation of the folliculin (FLCN) gene. This study was established to investigate the mutation of the FLCN gene and the phenotype in a family with PSP.Methods:We investigated the clinical and genetic characteristics of a large Chinese family with recurrent spontaneous pneumothorax. Genetic testing was performed by Sanger sequencing of the coding exons (4–14 exons) of the FLCN gene.Results:Among ten affected members in a multi-generational PSP kindred, with a total of 18 episodes of spontaneous pneumothorax, the median age for the initial onset of pneumothorax was 42.5 years (interquartile range: 28.8–57.2 years). Chest computed tomography scan of the proband showed pulmonary cysts and pneumothorax. A novel nonsense mutation (c.1273C>T) in exon 11 of FLCN gene that leads to a pre-mature stop codon (p.Gln425∗) was identified in the family. The genetic analysis confirmed the diagnosis of BHD syndrome in this family in the absence of skin lesions or renal tumors.Conclusions:A novel nonsense mutation of FLCN gene was found in a large family with PSP in China. Our results expand the mutational spectrum of FLCN gene in patients with BHD syndrome.

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Section: Discussionmentioning

confidence: 99%

“…[3] BHD syndrome is the most common genetic cause of familial pneumothorax, the accumulating familial cases have been confirmed to be associated with BHD syndrome. [4–9]…”

Section: Introductionmentioning

confidence: 99%

Recurrent primary spontaneous pneumothorax in a large Chinese family

Zheng

Gao

et al. 2019

Chinese Medical Journal

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“…Spontaneous pneumothorax shared between BHDS and PSP [24][25][26][27] is often the first presenting manifestation 28 and may be the only one of BHDS, [29][30][31] whereas, the skin findings generally appear in the fourth decade of FLCN mutant carriers and become progressively more noticeable with age. [32][33][34] The renal phenotype of BHDS is also a late finding when compared with pulmonary cysts/pneumothorax.…”

Section: Discussionmentioning

confidence: 99%

FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome

Min

Mao

Zou

et al. 2020

Thorax

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BackgroundBirt-Hogg-Dubé Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gene. Isolated cysts/pneumothorax is the most frequent atypical presentation of BHDS and often misdiagnosed as primary spontaneous pneumothorax (PSP). Deferential diagnosis of BHDS with isolated pulmonary presentation (PSP-BHD) from PSP is essential in lifelong surveillance for developing renal cell carcinoma.MethodsThe expression profiles of microRNAs (miRNAs) in cystic lesions of PSP-BHD and PSP were determined via microarray. The selected upregulated miRNAs were further confirmed in the plasma of an expanded cohort of PSP-BHD patients by reverse transcription quantitative PCR (RT-qPCR). Their diagnostic accuracy was evaluated. Moreover, the cellular functions and targeted signalling pathways of FLCN-regulated miRNAs were assessed in various cell lines and in the lesion tissue contexts.ResultsCystic lesions of PSP-BHD and PSP showed different miRNAs profiles with a significant upregulation of miR-424–5p and let-7d-5p in PSP-BHD. The combination of the two effectively predicted BHDS patients. In vitro studies revealed a suppressive effect of FLCN on miR-424–5p and let-7d-5p expressions specifically in lung epithelial cells. The ectopic miRNAs triggered epithelial apoptosis and epithelial transition of mesenchymal cells and suppressed the reparative responses in cells and tissues with FLCN deficiency.ConclusionThe upregulation of miR-424–5p and let-7d-5p by FLCN deficiency occurred in epithelial cells and marked the PSP-BHD condition, which contributed to a focused degenerative pathology in the lung of PSP-BHD patients.

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“…This novel variant is predicted to cause premature truncation of the FLCN protein, leading to functional haploinsufficiency of FLCN. Loss of function of this protein can cause alveolar enlargement and cysts formation, consequently leading to pneumothorax (Xing et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Pathogenic Folliculin Variant in a Chinese Family With Birt–Hogg–Dubé Syndrome (Hornstein-Knickenberg Syndrome)

Zong

Liu

et al. 2020

Front. Genet.

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Birt-Hogg-Dubé syndrome (BHDS), which is also called Hornstein-Knickenberg syndrome (HKS), is a hereditary autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN, NM_144997). More pulmonary manifestations (pulmonary cysts and recurrent pneumothoraxes) but fewer skin fibrofolliculomas and renal malignancy are found in Asian BHDS patients compared with other BHDS patients. The atypical manifestation can easily lead to a missed or delayed diagnosis. Here, we report a Chinese family with BHDS that presented with primary spontaneous pneumothorax (PSP) and extensive pulmonary cysts in the absence of skin lesions or renal neoplasms. Next-generation sequencing (NGS) was used to sequence the FLCN gene, and Sanger sequencing was carried out on the samples to confirm the presence of these variants. Among the 13 family members, a novel frameshift variant of FLCN (c.912delT/p.E305KfsX18) was identified in seven individuals. This variant has not been reported before. Bioinformatics analysis showed that the novel variant might lead to a premature stop codon after 18 amino acid residues in exon 9, and this may affect the expression level of FLCN. The identification of this novel frameshift variant of FLCN not only further confirms the familial inheritance of BHDS in the proband but also expands the mutational spectrum of the FLCN gene in patients with BHDS.

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Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax

Cited by 11 publications

References 28 publications

Recurrent primary spontaneous pneumothorax in a large Chinese family

Recurrent primary spontaneous pneumothorax in a large Chinese family

FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome

Identification of a Novel Pathogenic Folliculin Variant in a Chinese Family With Birt–Hogg–Dubé Syndrome (Hornstein-Knickenberg Syndrome)

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