On Birt-Hogg-Dubé syndrome: Cohorts, rare cases and novel genes

The research in this thesis consists of cohort studies, rare cases and novel genes for Birt-Hogg-Dubé syndrome (BHD) and BHD-like phenotypes. It was performed in the Amsterdam UMC, a national referral center for BHD. The Amsterdam UMC has one of the largest cohorts of BHD patients in the world, providing the opportunity to study relatively large patients cohorts and cases with remarkable features. In section 2.1, we found a pneumothorax risk of 0.63% per flight and 0.33% per episode of diving in patients with BHD. We concluded that diving is in general contra-indicated in BHD, but there is no need to advise against air travel in patients with BHD. In section 2.2, we found a 3.4% prevalence of BHD among 88 patients with an apparent primary spontaneous pneumothorax. We recommended to perform a chest CT in all patients with an apparent primary spontaneous pneumothorax. We evaluated renal surveillance techniques and compliance to renal surveillance in 199 BHD patients in section 3.1. We concluded that ultrasound might be a safe, cheap and widely available alternative for MRI in renal surveillance of BHD patients. Furthermore, the compliance to renal surveillance was relatively high. In section 3.2, we found no significant difference in the percentage of individuals with colorectal carcinoma when comparing BHD patients with their family members without BHD. However, there was a siginifcant difference between the number of individuals who had colorectal polyps removed. While not proven, we hypothesized that this was the result of more colonoscopies being performed in patients with BHD. In section 4.1, we describe a family of three with an exceptional phenotype of childhood renal cell carcinoma and brain tumors, caused by the combination of BHD and Li-Fraumeni syndrome. In section 4.2, we desscribe a new distinguishable syndrome characterized by extensive lipomatosis, fibrofolliculomas, mucosal lesions and renal cell carcinoma, caused by a variant in the PRDM10 gene. We showed that the variant in PRDM10 leads to the loss of affinity to bind the FLCN promotor, causing decreased expression of FLCN. The families described in section 4.3 had an initial diagnosis of BHD based on their skin phenotype, but the FLCN locus was excluded. We showed that affected patients from nine families share the same haplotype on chromosome 5, which includes a predicted truncating variant in the FNIP1 gene and a predicted missense variant in the PDGFRB gene. A zebrafish model for BHD had not been established yet and was described in section 5.1. The flcn mutant zebrafish were viable and had a severe developmental phenotype with decreased growth, morphological features and early death within two months of age. The cause of the early death was most likely a problem with energy homeostasis, since histologic abnormalities were observed in skeletal muscle, heart and liver and mitochondrial oxidative phosphorylation was decreased in isolated mitochondria. The BHD zebrafish model was subsequently used to study combined mutations of flcn and tp53 in section 5.2. We found no effect of the tp53 genotype on the flcn mutant phenotype. Furthermore, we found no effect of the flcn genotype (wild-type or heterozygous) on the tp53 phenotype