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Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD. We performed extensive clinical evaluations and genetic testing in ten families with FMDF. We identified a FNIP1 frameshift variant in nine families and genealogical studies showed common ancestry for eight families. Using whole exome sequencing, we identified six additional rare variants in the haplotype surrounding FNIP1, including a missense variant in the PDGFRB gene that was found to be present in all tested patients with FMDF. Genome-wide linkage analysis showed that the locus on chromosome 5 including FNIP1 was the only region reaching the maximal possible LOD score. We concluded that FMDF is linked to a haplotype on chromosome 5. Additional evaluations in families with FMDF are required to unravel the exact genetic cause underlying the phenotype. When evaluating patients with multiple trichodisomas without a pathogenic variant in the FLCN gene, further genetic testing is warranted and can include analysis of the haplotype on chromosome 5.

Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD. We performed extensive clinical evaluations and genetic testing in ten families with FMDF. We identified a FNIP1 frameshift variant in nine families and genealogical studies showed common ancestry for eight families. Using whole exome sequencing, we identified six additional rare variants in the haplotype surrounding FNIP1, including a missense variant in the PDGFRB gene that was found to be present in all tested patients with FMDF. Genome-wide linkage analysis showed that the locus on chromosome 5 including FNIP1 was the only region reaching the maximal possible LOD score. We concluded that FMDF is linked to a haplotype on chromosome 5. Additional evaluations in families with FMDF are required to unravel the exact genetic cause underlying the phenotype. When evaluating patients with multiple trichodisomas without a pathogenic variant in the FLCN gene, further genetic testing is warranted and can include analysis of the haplotype on chromosome 5.

In retrospective studies involving recurrent events, it is common to select individuals based on their event history up to the time of selection. In this case, the ascertained subjects might not be representative for the target population, and the analysis should take the selection mechanism into account. The purpose of this paper is two-fold. First, to study what happens when the data analysis is not adjusted for the selection and second, to propose a corrected analysis. Under the Andersen-Gill and shared frailty regression models, we show that the estimators of covariate effects, incidence, and frailty variance can be biased if the ascertainment is ignored, and we show that with a simple adjustment of the likelihood, unbiased and consistent estimators are obtained. The proposed method is assessed by a simulation study and is illustrated on a data set comprising recurrent pneumothoraces. Copyright © 2016 John Wiley & Sons, Ltd.

Contains fulltext : 171437.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: Birt-Hogg-Dube syndrome is an autosomal dominant disorder characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cell cancer due to germline folliculin (FLCN) mutations (Menko et al. in Lancet Oncol 10(12):1199-1206, 2009). The aim of this study was to evaluate the incidence of spontaneous pneumothorax in patients with BHD during or shortly after air travel and diving. METHODS: A questionnaire was sent to a cohort of 190 BHD patients and the medical files of these patients were evaluated. The diagnosis of BHD was confirmed by FLCN mutations analysis in all patients. We assessed how many spontaneous pneumothoraces (SP) occurred within 1 month after air travel or diving. RESULTS: In total 158 (83.2 %) patients returned the completed questionnaire. A total of 145 patients had a history of air travel. Sixty-one of them had a history of SP (42.1 %), with a mean of 2.48 episodes (range 1-10). Twenty-four (35.8 %) patients had a history of pneumothorax on both sides. Thirteen patients developed SP < 1 month after air travel (9.0 %) and two patients developed a SP < 1 month after diving (3.7 %). We found in this population of BHD patients a pneumothorax risk of 0.63 % per flight and a risk of 0.33 % per episode of diving. Symptoms possible related to SP were perceived in 30 patients (20.7 %) after air travel, respectively in ten patients (18.5 %) after diving. CONCLUSION: Based on the results presented in this retrospective study, exposure of BHD patients to considerable changes in atmospheric pressure associated with flying and diving may be related to an increased risk for developing a symptomatic pneumothorax. Symptoms reported during or shortly after flying and diving might be related to the early phase of pneumothorax. An individualized advice should be given, taking also into account patients' preferences and needs.

Background: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD. Methods: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families. Results: Among 14 FLCN mutation carriers who developed renal cancer 7 were

The development and natural course of lung cysts in patients with Birt-Hogg-Dube syndrome (BHD) is still unclear, and the relationship between lung cysts and pneumothorax is not fully clarified. Based on the follow-up results of thoracic imaging in six patients with BHD, we hypothesize that decreased potential for stretching of the cysts' wall and extensive contact with the visceral pleura are probably responsible for rupture of the cyst wall resulting in increased risk for pneumothorax.

Renal cell cancer (RCC) represents 2–3 % of all cancers and is the most lethal of the urologic malignancies, in a minority of cases caused by a genetic predisposition. Birt–Hogg–Dubé syndrome (BHD) is one of the hereditary renal cancer syndromes. As the histological subtype and clinical presentation in BHD are highly variable, this syndrome is easily missed. Lung cysts—mainly under the main carina—are reported to be present in over 90 % of all BHD patients and might be an important clue in differentiating between sporadic RCC and BHD associated RCC. We conducted a retrospective study among patients diagnosed with sporadic RCC, wherein we retrospectively scored for the presence of lung cysts on thoracic CT. We performed FLCN mutation analysis in 8 RCC patients with at least one lung cysts under the carina. No mutations were identified. We compared the radiological findings in the FLCN negative patients to those in 4 known BHD patients and found multiple basal lung cysts were present significantly more frequent in FLCN mutation carriers and may be an indication for BHD syndrome in apparent sporadic RCC patients.

In retrospective studies involving recurrent events, it is common to select individuals based on their event history up to the time of selection. In this case, the ascertained subjects might not be representative for the target population, and the analysis should take the selection mechanism into account. The purpose of this paper is two-fold. First, to study what happens when the data analysis is not adjusted for the selection and second, to propose a corrected analysis. Under the Andersen-Gill and shared frailty regression models, we show that the estimators of covariate effects, incidence, and frailty variance can be biased if the ascertainment is ignored, and we show that with a simple adjustment of the likelihood, unbiased and consistent estimators are obtained. The proposed method is assessed by a simulation study and is illustrated on a data set comprising recurrent pneumothoraces. Copyright © 2016 John WileySons, Ltd.

Contains fulltext : 152982.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Hip fracture patients of 65 years and older are a complex patient group who often suffer from complications and difficult rehabilitation with disappointing results. It is unknown to what extent suboptimal hospital care contributes to these poor outcomes. This study reports on the scale, preventability, causes and prevention strategies of adverse events in patients, aged 65 years and older, admitted to the hospital with a primary diagnosis of hip fracture. DESIGN, SETTING AND OUTCOME MEASURES: A retrospective record review study was conducted of 616 hip fracture patients (>/=65 years) admitted to surgical or orthopaedic departments in four Dutch hospitals in 2007. Experienced physician reviewers determined the presence and preventability of adverse events, causes and prevention strategies using a structured review form. The main outcome measures were frequency of adverse events and preventable adverse events in hospitalised hip fracture patients of 65 years and older, and strategies to prevent them in the future. RESULTS: 114 (19%) of the 616 patients in the study experienced one or more adverse events; 49 of these were preventable. The majority of the adverse events (70%) was related to the surgical procedure and many resulted in an intervention or additional treatment (67%). Human causes contributed to 53% of the adverse events, followed by patient-related factors (39%). Training and close monitoring of quality of care and the health professional's performance were the most often selected strategies to prevent these adverse events in the future. CONCLUSIONS: The high percentage of preventable adverse events found in this study shows that care for older hospitalised hip fracture patients should be improved. More training and quality assurance is required to provide safer care and to reduce the number of preventable adverse events in this vulnerable patient group.

We report a 56-year-old woman with a migrating foreign body in the digestive tract, eventually located at the prevertebral space. The foreign body was missed during outpatient flexible endoscopy. Most important complication is mediastinitis, clinically presenting as malaise, fever and pain between the scapulae.

Background Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominantly inherited disorder caused by germline mutations in the folliculin (FLCN) gene. Clinical manifestations of BHD include skin fibrofolliculomas, renal cell cancer, lung cysts and (recurrent) spontaneous pneumothorax (SP). All clinical manifestations usually present in adults > 20 years of age. Case presentations Two non-related patients with (recurrent) pneumothorax starting at age 14 accompanied by multiple basal lung cysts on thoracic CT underwent FLCN germline mutation analysis. A pathogenic FLCN mutation was found in both patients confirming suspected BHD. The family history was negative for spontaneous pneumothorax in both families. Conclusion Although childhood occurrence of SP in BHD is rare, these two cases illustrate that BHD should be considered as cause of SP in children.

In this case, we describe a patient with a history of recurrent pneumothorax. Based on CT-thorax and histopathology of the lung tissue, the Birt-Hogg-Dubé syndrome was suspected and confirmed after genetic testing. Recognizing this syndrome by pulmonologists and radiologists is very important, because the risk on developing of renal cell cancer is high.

Birt-Hogg-Dubé (BHD) syndrome is a cancer disorder caused by a pathogenicFLCNmutation characterized by fibrofolliculomas, lung cysts, pneumothorax, benign renal cyst, and renal cell carcinoma (RCC). In this case we describe a patient with bilateral renal tumour and a positive familial history for pneumothorax and renal cancer. Based on this clinical presentation, the patient was suspected for BHD syndrome, which was confirmed after molecular testing. We discuss the importance of recognizing this autosomal dominant cancer disorder when a patient is presented at the urologist with a positive family history of chromophobe renal cell cancer or a positive familial history for renal cell cancer and pneumothorax.

Johannesma PC, van der Klift HM, van Grieken NCT, Troost D, te Riele H, Jacobs MAJM, Postma TJ, Heideman DAM, Tops CMJ, Wijnen JT, Menko FH. Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations. Childhood brain tumours may be due to germline bi-allelic mismatch repair (MMR) gene mutations in MLH1, MSH2, MSH6 or PMS2. These mutations can also lead to colorectal neoplasia and haematological malignancies. Here, we review this syndrome and present siblings with early-onset rectal adenoma and papillary glioneural brain tumour, respectively, due to novel germline bi-allelic PMS2 mutations. Identification of MMR protein defects can lead to early diagnosis of this condition. In addition, assays for these defects may help to classify brain tumours for research protocols aimed at targeted therapies.

Background The clinical environment in which health care providers have to work everyday is highly complex; this increases the risk for the occurrence of unintended events. The aim of this randomised controlled trial is to improve patient safety for a vulnerable group of patients that have to go through a complex care chain, namely elderly hip fracture patients. Methods/design A randomised controlled trial that consists of three interventions; these will be implemented in three surgical wards in Dutch hospitals. One surgical ward in another hospital will be the control group. The first intervention is aimed at improving communication between care providers using the SBAR communication tool. The second intervention is directed at stimulating the role of the patient within the care process with a patient safety card. The third intervention consists of a leaflet for patients with information on the most common complications for the period after discharge. The primary outcome measures in this study are the incidence of complications and adverse events, mortality rate within six months after discharge and functional mobility six months after discharge. Secondary outcome measures are length of hospital stay, quality and completeness of information transfer and patient satisfaction with the instruments. Discussion The results will give insight into the nature and scale of complications and adverse events that occur in elderly hip fracture patients. Also, the implementation of three interventions aimed at improving the communication and information transfer provides valuable possibilities for improving patient safety in this increasing patient group. This study combines the use of three interventions, which is an innovative aspect of the study. Trial registration The Netherlands National Trial Register NTR1562

Spontaneous pneumothorax can be due to Birt-Hogg-Dubé syndrome (BHD syndrome), an autosomal dominant predisposition for fibrofolliculomas, multiple lung cysts, pneumothorax and renal cancer. The syndrome is the result of germline mutations in the FLCN (folliculin) gene. Its clinical presentation is highly variable. Consequently, this syndrome is probably under-diagnosed. An illustrative kindred is presented in which the index patient, a man aged 26, had recurrent episodes of pneumothorax without apparent skin lesions or renal abnormalities. He had bilateral mostly basally-located lung cysts. There was a family history of fibrofolliculomas, lung cysts, pneumothorax and clear cell renal cancer. Recognition of BHD is important since carriers of the mutation can be offered surveillance for early detection and treatment of renal cancer.

e15579 Background: Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant inherited disorder caused by mutations in the FLCN gene predisposing for renal cell cancer. Generally, surveillance of the ...

Aim: Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant condition due to germline mutations in the folliculin (FLCN) gene, clinically characterized by skin fibrofolliculomas, lung cysts, (recurrent) spontaneous pneumothorax (SP) and an increased risk of renal cell cancer (RCC). Families with BHD are most often identified through recognition of fibrofolliculomas A less common way to identify a BHD family is through (recurrent) SP. The characteristic pulmonary cystsare generally not visible on standard chest X-ray, and therefore will be missed in the standard – according to British Thoracic Society guidelines - diagnostic work-up for SP cases. We hypothesize that supplementing the diagnostic work-up of SP patients with CT imaging will result in the identification of BHD patients presenting with SP. This provides the opportunity of the identification of (asymptomatic) RCC at an early stage by screening of identified FLCN mutation carriers. Methods: We retrospectively collected clinical and radiological data of 55 families, including 200 BHD patients with a proven pathogenic FLCN mutation. Our database started in 2004; the mean follow-up time of mutation carriers is 5 years (1-10 years). Results: Sixty patients in 33 families had (recurrent) SP. In 14 out of 30 families we detected one or more patients with RCC. In total 19 patients had a history of RCC, 7 of them had a history of (recurrent) SP and 15 patients had a positive familial history for SP. We found in 14 cases RCC at an early stage, 5 patients died due metastases. Histological diagnosis were mainly (a combination of) clear cell carcinoma and chromophobe carcinoma. Conclusions: Based on these results, we suggest that including (low dose) thoracic CT in the standard SP work up should result in the identification of BHD families. In these families annual screening for RCC should be offered to affected relatives, which was shown to result in early detection of BHD associated RCC. We show that a limited period of observation of these families has resulted in detection of 14 patients with RCC at an early stage. Disclosure: All authors have declared no conflicts of interest.