BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, pulmonary cysts, and recurrent pneumothorax. Pulmonary cysts are the cause of recurrent pneumothorax, which is one of the most important factors influencing patient quality of life. It is unknown whether pulmonary cysts progress with time or influence pulmonary function in patients with BHD syndrome. This study investigated whether pulmonary cysts progress during long-term follow-up (FU) by using thoracic computed tomography (CT) and whether pulmonary function declines during FU. We also evaluated risk factors for pneumothorax in patients with BHD during FU.
METHODS: Our retrospective cohort included 43 patients with BHD (25 women; mean age, 54.2 ± 11.7 years). We evaluated whether cysts progress by visual assessment and quantitative volume analysis using initial and serial thoracic CT. The visual assessment included the size, location, number, shape, distribution, presence of a visible wall, fissural or subpleural cysts, and air-cuff signs. In CT data obtained from a 1-mm section from 17 patients, the quantitative assessment was performed by measuring the volume of the low attenuation area using in-house software. We evaluated whether the pulmonary function declined with time on serial pulmonary function tests (PFT). Risk factors for pneumothorax were analyzed using multiple regression analysis.
RESULTS: On visual assessment, the largest cyst in the right lung showed a significant interval increase in size (1.0 mm/year, p = 0.0015; 95% confidence interval [CI], 0.42-1.64) between the initial and final CT, and the largest cyst in the left lung also showed significant interval increase in size (0.8 mm/year, p < 0.001, 95% CI; -0.49-1.09). On quantitative assessment, cysts had a tendency to gradually increase in size. In 33 patients with available PFT data, FEV1pred%, FEV1/FVC, and VCpred% showed a statistically significant decrease with time (p < 0.0001 for each). A family history of pneumothorax was a risk factor for the development of pneumothorax.
CONCLUSIONS: The size of pulmonary cysts progressed over time in longitudinal follow-up thoracic CT in patients with BHD, and pulmonary function had slightly deteriorated by longitudinal follow-up PFT.

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.
Patients with BHD syndrome who had the following criteria were included: 1) tested for folliculin gene mutation, and 2) had at least one of the conditions: other specified malformation syndromes, fibrofolliculoma, acrochordon, lung cyst, cancer, and pneumothorax based on International Classification of Disease-10 code.
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.
The prevalence of BHD syndrome in Korea is extremely low. However, affected patients manifest several comorbidities, including malignant neoplasm and repetitive pneumothorax.

Birt-Hogg-Dube syndrome (BHDS) (MIM: 135150) is a rare autosomal dominant disorder with variable penetrance, caused by pathogenic variants in the FLCN gene. Only a few hundreds of families have so far been described in the literature. Patients with BHDS present with three distinct symptoms: fibrofolliculomas, pneumothorax due to lung cyst formation, and increased lifetime risk of kidney tumours. The aim of the current study was to estimate the incidence of BHDS in the Swedish population and further describe the clinical manifestations and their frequency. Splice variant c.779+1G>T was the most common pathogenic variant, found in 57% of the families, suggesting this may be a founder mutation in the Swedish population. This was further investigated using haplotype analysis in 50 families that shared a common haplotype. Moreover, according to gnomAD the carrier frequency of the c.779+1G>T variant has been estimated to be 1/3265 in the Swedish population, however our data suggest that the carrier frequency in the Swedish population may be significantly higher. These findings should raise awareness among physicians of different specialties to patients presenting with fibrofolliculomas, pneumothorax and/or kidney tumours. We also stress the importance of consensus recommendations regarding diagnosis and clinical management of this, not that uncommon, syndrome.

The diagnosis of patients with Birt-Hogg-Dubé (BHD) syndrome is always delayed (even for more than 10 years). Improving the understanding and diagnosis of this disease is vital for clinicians and radiologists. In this study we presented the chest computed tomography (CT) findings of BHD syndrome and offered suggestions for BHD cases with spontaneous pneumothorax.
Twenty-six BHD patients from 11 families (10 men, 16 women; mean age: 46 ± 12 years, 20-68 years) were included. The clinical features of the patients included pneumothorax, renal lesions, and skin lesions. Twenty-three patients underwent chest CT imaging. The cyst condition of each patient derived from reconstructed chest CT imaging was recorded, including the cyst number, size, volume, pattern, and distribution.
Pneumothorax occurred in 54% (14/26) of patients. Among them, 43% (6/14) had pneumothorax more than twice. However, typical skin and renal lesions were absent. Four patients had renal hamartoma. CT showed that 23 (100%) patients had lung cysts. Pulmonary cysts were bilateral and multiple, round, irregular, or willow-like. And 93.6% of the large cysts (long-axis diameter ≥ 20 mm) were under the pleura, and near the mediastinum and spine. The long-axis diameter, short-axis diameter and volume of the largest cysts were associated with the occurrence of pneumothorax (all P < 0.05).
Chest CT imaging can reveal some characteristic features of BHD syndrome. The occurrence of pneumothorax in BHD patients is closely related to their pulmonary cystic lesions.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominantly inherited cancer predisposition syndrome associated with an increased risk of spontaneous pneumothorax (SP) and renal cell carcinoma in the adult population. Recent studies suggest that BHD accounts for up to 10% of all SP in adults and BHD in children with SP have been reported.
To explore to what extent BHD is the cause of childhood pneumothorax, we studied a Danish BHD cohort consisting of 109 cases from 22 families. Clinical data was gathered by review of medical records. A systematic literature search concerning childhood and adolescence pneumothorax in BHD was performed and identified publications reviewed.
In our cohort, three of 109 BHD cases experienced childhood pneumothorax, corresponding to a prevalence of 3%. Reviewing the literature, data regarding more than 800 BHD cases were covered. Only seven previously published cases of childhood pneumothorax in BHD were identified.
Our findings suggest that BHD is likely the cause of a larger subset of childhood pneumothoraces than hitherto recognized. Awareness of BHD as a cause of childhood pneumothorax needs to be raised to provide patients and relatives with the possibility of specialized management of SP and regular renal cancer surveillance.

The Birt-Hogg-Dubé (BHD) syndrome is a very rare autosomal dominant form of genodermatosis caused by germline mutations in the folliculin (FLCN) gene, which is mapped to the p11.2 region in chromosome 17. BHD commonly presents cutaneous fibrofolliculomas, pulmonary cysts, renal cell carcinoma, and recurrent pneumothoraxes. The disease is easily ignored or misdiagnosed as pneumothorax, pulmonary lymphangiomyomatosis (LAM), or emphysema. Follow-up and guidelines for managing recurrent pneumothoraxes in these patients are lacking.
We reported the case of a 56-year-old Chinese woman who presented skin lesions, multiple lung bubblae, recurrent pneumothoraxes, thyroid nodules, and pulmonary inflammatory pseudotumors (PITs). The patient had a family history of pneumothoraxes and renal tumor. The BHD diagnosis was confirmed by genetic testing, which revealed a novel FLCN mutation in exon 14. Furthermore, the patient underwent a bullectomy because of recurrent pneumothorax 6 years ago.
To our knowledge, the novel mutation in exon 14 and the manifestation of PIT in the present case have never been reported for BHD. The patient underwent a bullectomy previously with no relapse at the last follow-up before the preparation of this report, thereby suggesting that thoracotomy with bullectomy may be a possible therapeutic approach for some BHD patients with recurrent pneumothorax.

Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disease characterised by benign cutaneous lesions, pulmonary cysts, and an increased risk of renal tumors. This rare condition is due to a mutation in the folliculin (FLCN) gene on chromosome 17q11.2, which has a role in the mechanistic/mammalian target of rapamycin (mTOR) signaling pathway of tumorigenesis. This case illustrates a patient with BHD and a renal angiomyolipoma, a neoplastic lesion not usually associated with BHD but common in Tuberous Sclerosis Complex (TSC). There is both clinical and molecular overlap between BHD and TSC, which may arise from similarities in function of the TSC and FLCN proteins in the mTOR pathway; this case further demonstrates this potential correlation. © 2016 Wiley Periodicals, Inc.

BACKGROUND: The Birt-Hogg-Dubé syndrome is a rare cancer susceptibility syndrome characterised by renal tumours, lung cysts and pneumothoraces, and fibrofolliculomas. It is caused by dominantly inherited mutations in FLCN. Our objective was to report renal tumour characteristics in a large series of patients with the Birt-Hogg-Dubé syndrome.
METHODS: We studied French Birt-Hogg-Dubé patients with a history of renal tumour.
RESULTS: We included 33 patients with 21 distinct germline FLCN mutations. Median age at diagnosis of first renal tumour was 46, and age varied from 20 to 83. Twenty cases had one renal tumour, the remainder had two or more tumours. Most cases (23/33, 70%) had oncocytoma or renal cell carcinoma of the chromophobe or hybrid chromophobe-oncocytoma type, three had clear cell carcinoma (9%), and the other seven had carcinoma of papillary, undifferentiated or undetermined histology. Four cases had metastatic disease, although none died of it.
CONCLUSIONS: Age at renal tumour diagnosis was highly variable, highlighting the need for regular surveillance from young adulthood to old age. Most cases had tumour types classically associated with Birt-Hogg-Dubé, i.e. oncocytoma or renal cell carcinoma of the chromophobe or hybrid type. Nevertheless, 9% had clear cell renal cell carcinoma. Geneticists, urologists and oncologists should therefore be alert to the possibility of Birt-Hogg-Dubé in patients with renal cell carcinoma of clear cell histology, especially if there are associated manifestations. Finally, the behaviour of metastatic carcinoma seemed more indolent than in sporadic renal cancers.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR). Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas) in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD.
METHODS: We performed a double blinded, randomised, facial left-right controlled trial of topical rapamycin 0.1% versus placebo in 19 BHD patients. Trial duration was 6 months. The primary outcome was cosmetic improvement as measured by doctors and patients. Changes in fibrofolliculoma number and size were also measured, as was occurrence of side effects.
RESULTS: No change in cosmetic status of fibrofolliculomas was reported in the majority of cases for the rapamycin treated (79% by doctors, 53% by patients) as well as the placebo treated facial sides (both 74%). No significant differences between rapamycin and placebo treated facial halves were observed (p = 1.000 for doctors opinion, p = 0.344 for patients opinion). No significant difference in fibrofolliculoma number or change in size of the fibrofolliculomas was seen after 6 months. Side effects occurred more often after rapamycin treatment (68% of patients) than after placebo (58% of patients; p = 0.625). A burning sensation, erythema, itching and dryness were most frequently reported.
CONCLUSIONS: This study provides no evidence that treatment of fibrofolliculomas with topical rapamycin in BHD results in cosmetic improvement.
BACKGROUND: ClinicalTrials.gov NCT00928798.

Resources for rare diseases are lacking. Patients do not have the information and support that they need, and researchers struggle to make progress due to a shortage of skills and collaborations within the field. One way to overcome these hurdles is to host annual Symposia, focused on a specific rare disease. Here, we use the example of Birt-Hogg-Dubé Symposia to discuss the practical issues of such meetings, including the importance of timing and the choice of invited speakers. We highlight the ways in which rare disease symposia can create a single community, removing barriers between patients, clinicians and researchers.