Birt-Hogg-Dubé Syndrome Research Articles

Percutaneous thermal ablation for renal cell carcinoma in patients with Birt–Hogg–Dubé syndrome

PurposeThe purpose of this study was to analyze the outcome of patients with Birt–Hogg–Dubé (BHD) syndrome who underwent percutaneous thermal ablation of renal cell carcinoma (RCC). Materials and methodsSix patients with genetically proven BHD syndrome who underwent one or more sessions of percutaneous thermal ablation for the treatment of RCC were included. There were 4 men and 2 women, with a mean age of 57.3±7.5 [SD] years (range: 44–67years). A total of 29 RCCs (1–16 tumors per patient) were treated during 20 thermal ablation sessions (7 with radiofrequency ablation and 13 with cryoablation). Outcomes of thermal ablation therapy were assessed, including technical success, adverse events, local tumor progression, development of metastases, survival after thermal ablation, and changes in renal function. ResultsTechnical success was achieved in all ablation sessions (success rate, 100%). No grade 4 or 5 adverse events were observed. All patients were alive with no distant metastasis during a median follow-up period of 54months (range: 6–173months). No local tumor progression was found. The mean decrease in estimated glomerular filtration rate during follow-up was 10.7mL/min/1.73m2. No patients required dialysis or renal transplantation. ConclusionRadiofrequency ablation and cryoablation show promising results for the treatment of RCCs associated with BHD syndrome. Percutaneous thermal ablation may be a useful treatment option for this rare hereditary condition.

The Relevance of Family History Taking in the Detection and Management of Birt-Hogg-Dubé Syndrome

Background: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal-dominant inherited disorder characterized by inactivation of the gene Folliculin (FLCN), pulmonary cysts with recurrent spontaneous pneumothorax, dermatological lesions, and an increased risk of developing renal malignancies. Objectives: We aimed to investigate the real prevalence of BHDS and its prevalence among patients with a familial history of pneumothorax. Methods: From July 2014 to December 2016, we consecutively studied all patients with spontaneous pneumothorax and a positive family history for the same condition referring to our Institution. The suspicious cases underwent genetic analysis of the BHDS-causative gene FLCN. FLCN-positive cases were further evaluated with routine blood tests, chest radiography, chest CT, abdominal MRI, and dermatological evaluation. Results: Among 114 patients admitted with spontaneous pneumothorax, 7 patients had a family history of pneumothorax, and 6/7 (85.7%) patients had positive genetic test for FLCN as well as 7/13 family members. Pulmonary cysts were found in all patients with a FLCN-positive genetic test. Most patients (10/13, 76.9%) had tiny pulmonary cysts less than 1 cm in diameter. The vast majority of cysts were intraparenchymal (12/13, 92.3%) and located in lower lobes. Dermatological lesions were found in 7/13 (54%) patients, renal cysts in 4/13 (31%) patients, and renal cancer in 1 (1/13, 7.7%) patient. Conclusions: Although BHDS is considered a rare disease, BHDS underlies spontaneous pneumothorax more often than usually believed, especially whenever a family history of pneumothorax is present. Diagnosis of BHDS is essential to start monitoring patients for the risk of developing renal malignancies.

Familial spontaneous pneumothorax: importance of screening for Birt-Hogg-Dubé syndrome.

The goal of this study was to investigate the prevalence of Birt-Hogg-Dubé (BHD) syndrome in patients with familial spontaneous pneumothorax (FSP) and the clinical characteristics of pneumothorax related to BHD syndrome compared with those of primary spontaneous pneumothorax. A total of 37 families diagnosed with FSP from 2007 to 2017 were enrolled in this study. The FLCN gene, which is responsible for BHD syndrome, was sequenced using the Sanger method in 25 probands. For the patients with confirmed BHD syndrome-related pneumothorax, clinical characteristics including the median onset age of pneumothorax, the male-to-female ratio, the mean height and body mass index (BMI) and the recurrence rate after different treatment modalities were obtained and compared with those of patients with primary spontaneous pneumothorax. Of the 25 probands with FSP, 16 [64.0%, 95% confidence interval (CI) 43.8-84.2%] harboured FLCN germline mutations. In the patients with BHD syndrome-related pneumothorax, the median onset age of pneumothorax was 34 years; the male-to-female ratio was 1.3:1; and the mean height and BMI were 167.0 ± 8.6 cm and 23.6 ± 3.4 kg/m2, respectively. These characteristics were significantly different from those in patients with primary spontaneous pneumothorax from the same centre. The recurrence rate of BHD syndrome-related pneumothorax after conservative therapy was 53.1% (95% CI 38.6-67.5%) compared with 9.1% (95% CI 0-19.4%) after surgical treatment. BHD syndrome is one of the most common causes of FSP. Patients with FSP should be recommended for mutation screening for the FLCN gene to facilitate early diagnosis and proper intervention.

Role of Radiologists in the Diagnosis of Unsuspected Birt-Hogg-Dubé Syndrome in a Tertiary Clinical Practice.

OBJECTIVE. Birt-Hogg-Dubé (BHD) syndrome is considered rare. Growing evidence indicates that it is underdiagnosed. The purpose of this study is to ascertain the impact of radiology reports that suggest the possibility of BHD syndrome on downstream management and a final diagnosis of BHD syndrome. MATERIALS AND METHODS. In this retrospective study, electronic medical records were searched to identify radiology reports suggesting the possibility of BHD syndrome in patients without a known or suspected diagnosis. Clinical and demographic information, the specialty of the ordering clinician, and imaging findings and confidence conveyed in the radiology report (with BHD syndrome listed as the most likely diagnosis versus one among several possibilities but not as the leading diagnosis) were recorded. The resultant downstream evaluations that were captured included referral for genetic evaluation and subsequent diagnosis of BHD. RESULTS. Between 2004 and 2016, radiologists suggested a diagnosis of BHD syndrome in 87 patients. Of these patients, 15% (13/87) underwent genetic evaluation, and 54% of those patients (7/13) had positive findings. Genetic evaluation was more likely for patients with a history of pneumothorax (p = 0.004) or involvement of the lungs and kidneys (p = 0.003). The urology department referred the highest percentage of patients (31% [4/13]) for genetic evaluation. CONCLUSION. Radiologists have a unique opportunity to suggest BHD syndrome, allowing appropriate genetic testing, screening, and counseling of patients and their families. Clinical presentation, including a history of pneumothorax and involvement of both the lungs and kidneys on imaging, may determine which patients are ultimately referred for genetic evaluation. We hope that increasing awareness that BHD syndrome is not so rare may lead to early diagnosis.

A case of Birt-Hogg-Dube syndrome presenting with a rare oncocytic non-secretory phaeochromocytoma

A case of Birt-Hogg-Dube syndrome presenting with a rare oncocytic non-secretory phaeochromocytoma

Isolated Cystic Lung Disease: An Algorithmic Approach to Distinguishing Birt-Hogg-Dubé Syndrome, Lymphangioleiomyomatosis, and Lymphocytic Interstitial Pneumonia.

OBJECTIVE. Birt-Hogg-Dubé (BHD) syndrome, lymphangioleiomyomatosis (LAM), and lymphocytic interstitial pneumonia (LIP) frequently present as isolated cystic lung disease and can be challenging to distinguish. If imaging findings are otherwise unremarkable, the radiologist is unaided by ancillary CT findings in narrowing the diagnosis. We hypothesized that the distribution and morphologic features of lung cysts could be used to differentiate BHD syndrome, LAM, and LIP. Therefore, the purpose of this study was to characterize the CT appearances of these conditions and create a practical CT-based algorithm to differentiate among them. MATERIALS AND METHODS. The study was a retrospective review of the CT images of 16 patients with BHD syndrome, 17 patients with LAM, and 14 patients with LIP. On the basis of the data collected, a CT-based algorithm was created, and the CT images were reviewed again. RESULTS. Lower lung-predominant cysts were significantly more likely to be found in patients with BHD syndrome (100% of patients) or LIP (71-93% of patients) than in patients with LAM (6-12% of patients), who were more likely to have diffuse cysts. Compared with patients with LIP or LAM, patients with BHD syndrome were significantly more likely to have elliptical (floppy) paramediastinal cysts (88-94% of patients with BHD syndrome, 36-43% of patients with LIP, and 6-12% of patients with LAM) or a disproportionate number of paramediastinal cysts (69-88% of patients with BHD syndrome, 0-14% of patients with LIP, and 0-6% of patients with LAM). Our algorithm enabled differentiation of BHD syndrome, LAM, and LIP with a high level of accuracy and high interreader agreement (κ = 0.809). CONCLUSION. Radiologists can use the proposed CT-based algorithm to prospectively and confidently suggest one of these disorders as the favored diagnosis. Of importance, this will allow diagnosing the disorder early and accurately, screening for comorbidities, and prevention of potential complications.

Pathology of Birt-Hogg-Dubé syndrome: A special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review.

Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts and renal cell carcinomas. Affected individuals inherit germline mutations in the folliculin gene (FLCN). Approximately 150 pathogenic FLCN variants have been identified worldwide. Many Japanese probands of BHD syndrome were first identified by pulmonologists and/or radiologists during treatment of pneumothoraces. Lung specimens obtained through video-assisted thoracoscopic surgery (VATS) have characteristic features unique to BHD syndrome; however, pathologists often miss key findings and diagnose patients with "bullae/blebs". The pleural and subpleural cysts of BHD syndrome-associated lung diseases are often modified by tissue remodeling and can be difficult to distinguish from emphysematous bullae/blebs. Intraparenchymal unruptured cysts tend to retain distinctive features that are different from other cystic lung diseases. Here, we review the clinicopathological findings of BHD syndrome in a Japanese population based on data from 200 probands diagnosed by genetic testing and a total of 520 symptomatic family members identified through BHD-NET Japan (http://www.bhd-net.jp/). Detailed morphology of pulmonary cysts obtained from VATS and autopsied lung specimens are described, and pathological clues for differentiating miscellaneous cystic lung disorders are discussed.

Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, pneumothorax, fibrofolliculomas and renal cell cancer. The diagnosis of BHDS is usually considered if kidney cancer occurs before age 50 years, is multifocal and/or bilateral or of the oncocytoma/hybrid oncocytoma-chromophobe type. Using a sample of 50 BHDS families with a total of 178 patients we analyzed how many kidney cancer patients fulfilled one or more of these criteria. Furthermore, we addressed the question if genotype-phenotype-correlations exist that can be used for risk stratification. Renal cell cancer occurred in 34/178 (19.1%) patients, and the reported male bias was not observed. Furthermore, most kidney malignancies occurred after the age of 50 years. Thus, the majority of tumors did not show the typical hallmarks of BHDS. A below-average tumor frequency (17.2%) was observed for the known mutational hotspot c.1285delC/dupC that was the cause of BHDS in 24% of families. Unexpected was the high tumor frequency (66.7%) associated with mutation c.887C>G within a single family, a finding that merits further exploration.

Birt-Hogg-Dubé syndrome in the elderly.

We present the case of a 73-year-old woman who developed pneumothorax for the first time that was a clinical clue to the diagnosis of Birt-Hogg-Dubé (BHD) syndrome. Although younger onset of pneumothorax is more common in BHD syndrome, the characteristic chest CT findings may contribute to the diagnosis of this disorder in spontaneous pneumothorax of the elderly.

A Rare Cause of Recurrent Spontaneous Pneumothorax: Birt-Hogg-Dube Syndrome.

Birt-Hogg-Dube (BHD) syndrome is an unusual disorder characterized by the triad of cutaneous lesions, renal tumors and lung cysts. In cases with BHD syndrome, the frequency of recurrent pneumothorax is increased due to presence of multiple lung cysts. It is important to evaluate the BHD syndrome in differential diagnosis of recurrent pneumothorax especially with multiple lung cysts predominating in the lung base. In these patients, the presence of accompanying kidney and other tumors should be investigated. Herein, we report a case of BHD syndrome presenting with recurrent pneumothorax.

PO-102 Understanding the role of the tumour suppressor, FLCN, in renal tumorigenesis

IntroductionOur basic understanding of renal cell carcinoma (RRC) in the general population is limited. To gain a better understanding of how RRC develops, I took advantage of a genetic model of kidney cancer that mirrors a genetic disease called Birt-Hogg-Dubé (BHD) syndrome. BHD patients have an increased risk of developing kidney cancer, and unlike other genetic disorders with a predisposition to RRC, BHD patients are prone to all tumour subtypes. These patients are born with inactivating mutations within a gene called Folliculin (FLCN), a tumour suppressor protein of unknown function that could be involved in monitoring DNA damage.Material and methodsTo better define the tumour suppressor role of FLCN, I carried out a protein-protein interaction using FLCN as bait, which revealed that FLCN interacts with the DNA-damage response machinery. To further explore FLCN involvement in DNA damage, I used RNAi to generated FLCN knockdown in human proximal tubule kidney cells – which are thought to be the origin cells of BHD associated renal tumours – and performed basic cellular experiment such as western blot and flow cytometry.Results and discussionsI discovered that FLCN interacts with DNA-PKcs, a DNA damage component that is responsible for repairing double strand DNA (dsDNA) breaks. This is an important advancement, as it now implicates FLCN in the maintenance of DNA. The association of FLCN with DNA-PKcs weakens when cells are subjected to DNA damage. As a consequence of FLCN loss of function, kidney cells accumulate DNA damage and the activity of DNA damage response pathways are elevated. I also have evidence showing that a perturbed G1/S check point in FLCN-deficient cells which is a known driver of cancer progression.ConclusionUltimately, my work highlights a novel role of FLCN within renal cell tumourgenesis, suggesting it functions to prevent genomic instability. Genetic conditions, such as BHD that predispose individuals to cancer, while rare themselves, provide valuable insight into somatic tumour development. By using BHD syndrome as a model of genetic instability, further work will be carried out to mechanistically establish FLCN’s role in DNA integrity and will provide valuable insight into sporadic renal cancer within the general population.

Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation.

Birt-Hogg-Dube’ Syndrome (BHDS) is a rare genetic disorder in humans characterized by skin hamartomas, lung cysts, pneumothorax, and increased risk of renal tumors. BHDS is caused by mutations in the BHD gene, which encodes for Folliculin, a cytoplasmic adapter protein that binds to Folliculin interacting proteins-1 and -2 (Fnip1, Fnip2) as well as the master energy sensor AMP kinase (AMPK). Whereas kidney-specific deletion of the Bhd gene in mice is known to result in polycystic kidney disease (PKD) and renal cell carcinoma, the roles of Fnip1 in renal cell development and function are unclear. In this study, we utilized mice with constitutive deletion of the Fnip1 gene to show that the loss of Fnip1 is sufficient to result in renal cyst formation, which was characterized by decreased AMPK activation, increased mTOR activation, and metabolic hyperactivation. Using RNAseq, we found that Fnip1 disruption resulted in many cellular and molecular changes previously implicated in the development of PKD in humans, including alterations in the expression of ion and amino acid transporters, increased cell adhesion, and increased inflammation. Loss of Fnip1 synergized with Tsc1 loss to hyperactivate mTOR, increase Erk activation, and greatly accelerate the development of PKD. Our results collectively define roles for Fnip1 in regulating kidney development and function, and provide a model for how loss of Fnip1 contributes to PKD and perhaps renal cell carcinoma.

Air Travel-Related Spontaneous Pneumothorax in Diffuse Cystic Lung Diseases.

Spontaneous pneumothorax (SP) is a common manifestation of patients with diffuse cystic lung diseases (DCLDs) such as lymphangieoleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH) and Birt-Hogg-Dubé syndrome (BHD). Air travel may pose an additional risk for the development of SP. Here, we summarize the literature pertaining to air travel related SP in DCLDs in order to assist patients and clinicians in appropriate decision-making with regards to air travel. Several recent studies have estimated that the per-flight risk of SP in patients with DCLDs is approximately 1%, with disease-specific risk estimates of 1.1-2.6% in LAM, 0-0.63% in BHD, and 0.37% in PLCH. In general, it should be safe for most patients with DCLDs to undertake air travel. Patients should be counseled to seek medical attention and not board the airplane in the presence of sudden/new onset chest pain and/or dyspnea prior to boarding the plane.

Birt-Hogg-Dubé syndrome: an underdiagnosed genetic tumor syndrome.

Birt-Hogg-Dubé syndrome (BHD, also referred to as Hornstein-Knickenberg syndrome) is an autosomal dominant tumor syndrome caused by mutations in the FLCN gene located on chromosome17. Depending on their age, patients with BHD may exhibit various clinical signs and symptoms. Disease severity can vary greatly among members of the same family. Early symptoms include basal lung cysts, which can lead to recurrent spontaneous pneumothoraces. The majority of patients (>90%) develop multiple fibrofolliculomas, especially on the face and upper trunk, in the second or third decade of life. Given the 12-34% lifetime risk of developing benign or malignant renal tumors, targeted screening programs are prognostically crucial. While these renal tumors may belong to various histological subtypes, common variants include multifocal - sometimes bilateral - chromophobe and oncocytic hybrid tumors. Early diagnosis and adequate long-term care of families with BHD require interdisciplinary cooperation.

Primary Spontaneous Pneumothorax: Looking Beyond the Usual

Primary Spontaneous Pneumothorax: Looking Beyond the Usual

胸腔鏡手術を契機に診断に至ったBirt-Hogg-Dube症候群の1例

Birt-Hogg-Dube症候群は皮膚病変，腎腫瘍，気胸を特徴とする常染色体優性遺伝の疾患である．症例は62歳女性．左気胸と診断され当院紹介となる．両側の気胸の既往があり，母方の叔母，叔父に気胸の家族歴があった．胸腔鏡下左肺囊胞切除を施行，病理組織所見では囊胞壁は極めて菲薄な胸膜壁と肺胞壁からなっており，肺胞壁側は小葉間間質から成っていた．囊胞壁に突出する血管を認め，Birt-Hogg-Dube症候群が疑われた．遺伝子検査を行ったところfolliculin（FLCN）遺伝子に変異を認め，Birt-Hogg-Dube症候群と診断した．Birt-Hogg-Dube症候群の肺囊胞は自然気胸と異なり，中葉，舌区，下葉に好発する等の画像的特徴もあり，多発肺囊胞を伴う非典型的な気胸を発症した場合，Birt-Hogg-Dube症候群を念頭に置き気胸再発の可能性を考慮した術式を選択すべきと考えられた．

A case of Tuberous Sclerosis Complex Masquerading as Birt-Hogg-Dubé Syndrome

Tuberous sclerosis complex (TSC) and Birt-Hogg-Dube syndrome (BHDS) act via the mammalian target of rapamycin (mTOR) pathway, resulting in overlapping clinical presentations. We report a patient who presented with features suggestive of BHDS: multiple fibrofolliculomas, a history of spontaneous pneumothorax and a positive family history of a renal condition. Subsequent genetic testing confirmed a Tuberous sclerosis complex 2 (TSC2) gene mutation, corresponding to a diagnosis of TSC. This case highlights how closely intertwined both conditions are, and also confirms that fibrofolliculomas are a feature of TSC.

Dermatopathologic emergencies part ii: Dermatopathologic and situational

In dermatopathology, there are several conditions which must be addressed emergently. While some conditions necessitate emergent intervention because of the pathology of the cutaneous manifestations, others require recognition of the underlying serious systemic conditions represented by the cutaneous signs and symptoms. In this part, we address rickettsial infections and eczema herpeticum as diseases which should be addressed immediately on presentation because of the seriousness and rapidity of progression of their pathology. Moreover, porphyria cutanea tarda, Birt–Hogg–Dube syndrome, Muir–Torre syndrome, and acquired ochronosis may exemplify conditions where the cutaneous signs serve as warnings for severe systemic disease that may not be emergencies in isolation but can indicate rapid occult development of destructive and sometimes deadly noncutaneous pathology. The literature review was conducted using searches in PubMed and references to textbooks on the subjects.

Difference of the progression of pulmonary cysts assessed by computed tomography among COPD, lymphangioleiomyomatosis, and Birt-Hogg-Dubé syndrome.

Many groups developed the methods to quantitatively analyze low attenuation area (LAA) on chest CT in patients with cystic lung diseases. Especially in COPD, it was reported that the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D, which reflect the fractal dimension of terminal airspace geometry. We hypoyhesized that the quantitative charateristics of LAA clusters including fractal property might indicate the different features of the progression of cysts in cystic lung diseases. The aim of this study was to apply the CT image-based method of characterizing the size distribution of LAA clusters for lymphangioleiomyomatosis (LAM) and Birt-Hogg-Dubé syndrome (BHDS) to disclose their features of the progression of pulmonary cysts. 40 patients with COPD, 52 patients with LAM, and 18 patients with BHDS who had undergone CT scans at our institute between January 2002 and August 2009 were included. Differences among these diseases in the quantitative characteristics of LAA clusters {i.e., extent, number, size, fractal property, and the relationship between these quantitatives} were assessed. The Chi-sqsuare test, unpaired t-test, and one-way analyses of variance with Tukey post-hoc tests were used to compare groups, spline model with an interaction terms were used to assess the relationship between extent and number, and exponential regression model was used to assess the relationship between extent and size. Statistically significant differences separated the three diseases in extent and number (P < 0.001). Number was significantly correlated with extent in COPD (P < 0.001), but was not so in LAM and BHDS when extent exceeded 11.5% and 20.8%, respectively. Size was significantly correlated with extent in COPD and LAM (P < 0.001), but was not so in BHDS. The percentage of CT images with fractal property was higher in COPD than that in LAM and BHDS (95.8%, 92.9% and 63.0%, respectively). In conclusion, our study has demonstrated for the first time the different characteristics of the size distribution of LAA clusters among COPD, LAM and BHDS, and indicated that this method is useful for exploration of the pathophysiology in cystic lung diseases.

A FAMILIAL CASE OF BIRT‐HOGG‐DUBE SYNDROME (BHDS) COMPLICATED WITH BLADDER CANCER AND LUNG CANCERA CASE REPORT AND LITERATURE REVIEW

RespirologyVolume 22, Issue S3 p. 24-24 Clinical Respiratory Medicine 1 A FAMILIAL CASE OF BIRT-HOGG-DUBE SYNDROME (BHDS) COMPLICATED WITH BLADDER CANCER AND LUNG CANCERA CASE REPORT AND LITERATURE REVIEW First published: 23 November 2017 https://doi.org/10.1111/resp.13206_49Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume22, IssueS3Supplement: 22nd Congress of the Asian Pacific Society of Respirology, International Convention Centre, Sydney, Australia, 23–26 November 2017November 2017Pages 24-24 RelatedInformation