Epidemiology and Clinical Features of Birt-Hogg-Dubé Syndrome: A Nationwide Population-Based Study in South Korea

Background Birt–Hogg–Dubé (BHD) syndrome is an ultrarare lung disease with unclear prevalence and incidence. Our study aimed to identify the epidemiological and clinical features of BHD syndrome by using nationwide claims data from the Korean Health Insurance Review and Assessment service. Results We found 26 patients with BHD syndrome from 2017 to 2019. The prevalence of BHD syndrome was 5.67 per 107 population, with no peak age. Among incidence cases, the median age of diagnosis was 51 years, with slightly more females than males (n = 15, 57.7%). Over half of the patients (n = 14, 53.8%) experienced pneumothorax, and 10 (38.5%) developed malignant neoplasm within the clinical course. Conclusions The prevalence of BHD syndrome in Korea is extremely low. However, affected patients manifest several comorbidities, including malignant neoplasm and repetitive pneumothorax.

Clinical Characteristics and Genetic Analysis of Birt-Hogg-Dubé Syndrome With Congenital Contractural Arachnodactyly in a Family

Background Birt-Hogg-Dubé Syndrome (BHD syndrome) and congenital contractural arachnodactyly (CCA) or Beals Hecht Syndrome (BHS) are clinically rare autosomal dominant genetic diseases. In this study, we find an extremely rare family with BHD Syndrome with CCA.Objective To investigate the clinical and genetic variation characteristics of a family with BHD Syndrome with CCA.Methods The patient was examined for chest Computed Tomography (CT), abdominal and heart color ultrasound, rheumatism immune-related indexes, and hand Direct Digital Radiography (DR), and Whole Exome Sequencing (WES) was performed on family members.Results The proband, male, developed symptoms of chest tightness and shortness of breath, accompanied by irritant cough 2 years ago, and then repeated spontaneous pneumothorax four times. Chest CT showed: spontaneous pneumothorax on the right side, emphysema in both lungs, and bullae in both lungs. No manifestations of kidney tumors and skin lesions. His son had a history of pulmonary bullobes and occurred spontaneous pneumothorax twice. He, his mother, and his son were all born with a hand deformity. Sequencing results showed that both the proband and his son were folliculin (FLCN) gene c.1015C>T（p.Gln339Ter） heterozygous variation, Fibrillin 2 gene (FBN2) gene c.3485G>A（p.Cys1162Tyr） heterozygous variation, associated with BHD syndrome and CCA.Conclusion For patients with chest tightness, shortness of breath, recurrent spontaneous pneumothorax, and congenital hand deformity without inducement, genetic testing should be carried out as soon as possible to make a clear diagnosis, which can guide treatment and genetic counseling.

Clinical characteristics and genetic analysis of familial spontaneous pneumothorax in China

Familial spontaneous pneumothorax (FSP) is a hereditary disease, and Birt-Hogg-Dubé (BHD) syndrome is its main cause. FSP is an autosomal dominant genetic disease related to folliculin (FLCN). The goal of this study was to investigate the clinical characteristics and possible causes of FSP in China compared with those of primary spontaneous pneumothorax (PSP). We reviewed the detailed clinical data of 8 FSP patients in a family and analyzed the clinical characteristics of FSP combined with literatures. The FLCN gene of these 8 FSP patients was sequenced by the next-generation sequencing technology (NGS). The results showed that the clinical features of FSP were significantly different from those of PSP: the incidence of pneumothorax in women is significantly higher, and the age of pneumothorax is later, most of them are two generations, which may be related to heredity. And the effect of surgical treatment is the best. Novel nonsense mutation was found in the 8 patients, and the 8 patients had the same mutation, thus demonstrating the diversity of mutation spots along the gene. Therefore, the FLCN gene screening and early surgical intervention is recommended for FSP patients.

Birt Hogg Dube Syndrome and Thyroid Cancer - Is There an Association?

A 71-year-old man presented for evaluation of thyroid nodules. Past medical history includes auricular trichodiscoma/fibrofolliculomas and colon cancer at age 39. He underwent genetic testing revealing mutations of the CHEK2 and FLCN gene, conferring a diagnosis of Birt-Hogg-Dube syndrome (BHD). Subsequently, several family members were diagnosed with this syndrome. He was initially seen for evaluation of chronic cough. A neck ultrasound showed suspicious thyroid nodules and fine needle aspiration revealed suspicion for papillary thyroid cancer. He had molecular testing by AFIRMA and was GSC negative. He underwent right hemithyroidectomy and then completion with findings of a right lobe follicular thyroid carcinoma. Given underlying history of BHD, genetic testing was performed to assess for additional mutations that could predispose to thyroid cancer. This may help to raise awareness of screening for the presence of thyroid nodules and possibly thyroid carcinoma in individuals with BHD. Birt-Hogg-Dube (BHD) syndrome is a rare, autosomal dominant syndrome caused by a germline mutation in the FLCN gene, and is characterized by the presence of fibrofolliculomas, pneumothorax, and renal tumors. Thyroid nodules have been associated with BHD, present in 65% of individuals and 90% of families with this syndrome, however connection between BHD and thyroid cancer has not been established. For our patient, the most significant finding after a 170-gene panel analysis was an NRAS Q61R mutation. Mutations in RAS genes may be found in 15-20% of papillary thyroid cancers, 40-50% of follicular cancers, and 20-40% in follicular adenomas, and indicate poor prognosis. A CHEK2 mutation was also identified, which has been associated with an increased risk of multiple cancers, including thyroid. In addition, he had coding variants in the ATR gene on chromosome 3, as well as the IDH2 gene on chromosome 13. IDH2 may have a role in the development of thyroid cancer, however the contribution of these variants to tumor development or progression is currently unknown. For our patient, there is no published data to our knowledge regarding the findings of his coding variants and their possible association to BHD syndrome. More research needs to be done to assess for additional mutational variations present in those with BHD syndrome that may predispose to the development of thyroid cancer. Hara, H et al. “N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma.” Surgery vol. 116,6 (1994): 1010-6.

Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways

Folliculin (FLCN) is a tumor suppressor gene responsible for the inherited Birt-Hogg-Dubé (BHD) syndrome, which affects kidneys, skin and lungs. FLCN is a highly conserved protein that forms a complex with folliculin interacting proteins 1 and 2 (FNIP1/2). Although its sequence does not show homology to known functional domains, structural studies have determined a role of FLCN as a GTPase activating protein (GAP) for small GTPases such as Rag GTPases. FLCN GAP activity on the Rags is required for the recruitment of mTORC1 and the transcriptional factors TFEB and TFE3 on the lysosome, where mTORC1 phosphorylates and inactivates these factors. TFEB/TFE3 are master regulators of lysosomal biogenesis and function, and autophagy. By this mechanism, FLCN/FNIP complex participates in the control of metabolic processes. AMPK, a key regulator of catabolism, interacts with FLCN/FNIP complex. FLCN loss results in constitutive activation of AMPK, which suggests an additional mechanism by which FLCN/FNIP may control metabolism. AMPK regulates the expression and activity of the transcriptional cofactors PGC1α/β, implicated in the control of mitochondrial biogenesis and oxidative metabolism. In this review, we summarize our current knowledge of the interplay between mTORC1, FLCN/FNIP, and AMPK and their implications in the control of cellular homeostasis through the transcriptional activity of TFEB/TFE3 and PGC1α/β. Other pathways and cellular processes regulated by FLCN will be briefly discussed.

Characterization of CT scans of patients with Birt-Hogg-Dubé syndrome compared with those of Chinese patients with non-BHD diffuse cyst lung diseases

Background and objective: The purpose of this study was to create a practical CT-based algorithm to differentiate Birt-Hogg-Dubé (BHD) syndrome from other diffuse cystic lung diseases (DCLD).Methods: The study was a retrospective review of the CT images of 33 patients with BHD syndrome, 33 patients with LAM, and 23 patients with NBNL (non-BHD and non-LAM) among DCLD patients. On the basis of the data collected, the CT images were reviewed again to evaluate the characteristics (size, number, distribution, and morphology) of pulmonary cysts.Results: Lower lung-predominant cysts were more likely to be found in patients with BHD syndrome than in patients with LAM or in the NBNL DCLD group. In the axial distribution, 18 of 33 patients in BHD group had cysts that were predominantly near the mediastinum, and all the patients in the LAM and NBNL DCLD groups had diffuse cysts. The appearance of fusiform cysts was more easily observed in patients in the BHD group. In total, 58% patients in the BHD group had less than 50 lung cysts, while all patients in the non-BHD group had more than 50 lung cysts. The biggest cyst was located in the lower lobe in 28 of 33 patients in the BHD group, while 11 of 33 patients in LAM group and 10 patients in the NBNL DCLD group had the biggest cyst in the lower lobe.Conclusion: The pulmonary cysts in patients with BHD tended to be fusiform, less numerous and located predominantly in the lower lobe and near the mediastinum. These radiologic pulmonary features could assist physicians in differentiating BHD from other DCLDs.

Characterization of CT scan in Birt-Hogg-Dubé syndrome compared with non-BHD diffuse cysts lung diseases in Chinese Patients

Background and objective: The purpose of this study was to create a practical CT-based algorithm to differentiate Birt-Hogg-Dubé (BHD) syndrome from other diffuse cystic lung diseases (DCLD). Methods: The study was a retrospective review of the CT images of 18 patients with BHD syndrome, 18 patients with LAM, and 16 patients with NBNL (non-BHD and non-LAM) DCLD patients. On the basis of the data collected, the CT images were reviewed again to evaluate the characteristics (size, number, distribution, morphology) of pulmonary cysts. Results: Lower lung–predominant cysts were prone to be found in patients with BHD syndrome than in patients with LAM, but there is no difference between BHD and NBNL DCLD group. In the axial distribution, 9 of 18 patients in BHD-group had cysts predominance near the mediastinum, relatively, all the patients in the non-BHD group have diffuse cysts. The appearance of fusiform cysts was easier observed in patients of BHD group. Most patients in BHD-group had less than 50 lung cysts, while all patients in non-BHD group had more than 50 lung cysts. The maximum cyst located in the lower lobe in 16 of 18 patients in BHD-group, while 6 of 18 patients in LAM group and 8 patients in NBNL DCLD group had the maximum cyst in the lower lobe. Conclusion: The pulmonary cysts in patients with BHD tend to be fusiform, less numerous, and have a predominance in the lower lobe and near the mediastinum. These radiologic pulmonary features could assist physicians differentiating BHD from other DCLDs.

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

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.

Birt-Hogg-Dubé Syndrome: A Case Report Describing Sonographic Evaluation of Salivary Gland Oncocytomas

Birt-Hogg-Dubé (BHD) syndrome is a rare hereditary disorder associated with autosomal dominant hereditary epithelial carcinomas, in which patients have an increased incidence of renal cell carcinomas, scattered hamartomas, pulmonary cysts, and spontaneous pneumothoraces. Other less common findings include lipomas, parathyroid adenomas, salivary gland tumors, and colonic polyps/tumors. Early diagnosis of BHD can help establish renal screening and reduce mortality by early detection and more effective treatment of renal cell carcinoma. This case report describes the sonographic features of salivary gland oncocytomas found in a patient with BHD.

Loss of FLCN inhibits canonical WNT signaling via TFE3

Lower lobe predominant pulmonary cysts occur in up to 90% of patients with Birt–Hogg–Dubé (BHD) syndrome, but the key pathologic cell type and signaling events driving this distinct phenotype remain elusive. Through examination of the LungMAP database, we found that folliculin (FLCN) is highly expressed in neonatal lung mesenchymal cells. Using RNA-Seq, we found that inactivation of Flcn in mouse embryonic fibroblasts leads to changes in multiple Wnt ligands, including a 2.8-fold decrease in Wnt2. This was associated with decreased TCF/LEF activity, a readout of canonical WNT activity, after treatment with a GSK3-α/β inhibitor. Similarly, FLCN deficiency in HEK293T cells decreased WNT pathway activity by 76% post-GSK3-α/β inhibition. Inactivation of FLCN in human fetal lung fibroblasts (MRC-5) led to ~ 100-fold decrease in Wnt2 expression and a 33-fold decrease in Wnt7b expression—two ligands known to be necessary for lung development. Furthermore, canonical WNT activity was decreased by 60%. Classic WNT targets such as AXIN2 and BMP4, and WNT enhanceosome members including TCF4, LEF1 and BCL9 were also decreased after GSK3-α/β inhibition. FLCN-deficient MRC-5 cells failed to upregulate LEF1 in response to GSK3-α/β inhibition. Finally, we found that a constitutively active β-catenin could only partially rescue the decreased WNT activity phenotype seen in FLCN-deficient cells, whereas silencing the transcription factor TFE3 completely reversed this phenotype. In summary, our data establish FLCN as a critical regulator of the WNT pathway via TFE3 and suggest that FLCN-dependent defects in WNT pathway developmental cues may contribute to lung cyst pathogenesis in BHD.