title: Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.
abstract: 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 <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas.
  
  
  CONCLUSIONS
  We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A C
authors.initials: AC
authors.lastname: Houweling
authors.forename: L M
authors.initials: LM
authors.lastname: Gijezen
authors.forename: M A
authors.initials: MA
authors.lastname: Jonker
authors.forename: M B A
authors.initials: MB
authors.lastname: van Doorn
authors.forename: R A
authors.initials: RA
authors.lastname: Oldenburg
authors.forename: K Y
authors.initials: KY
authors.lastname: van Spaendonck-Zwarts
authors.forename: E M
authors.initials: EM
authors.lastname: Leter
authors.forename: T A
authors.initials: TA
authors.lastname: van Os
authors.forename: N C T
authors.initials: NC
authors.lastname: van Grieken
authors.forename: E H
authors.initials: EH
authors.lastname: Jaspars
authors.forename: M M
authors.initials: MM
authors.lastname: de Jong
authors.forename: E M H F
authors.initials: EM
authors.lastname: Bongers
authors.forename: P C
authors.initials: PC
authors.lastname: Johannesma
authors.forename: P E
authors.initials: PE
authors.lastname: Postmus
authors.forename: R J A
authors.initials: RJ
authors.lastname: van Moorselaar
authors.forename: J-Htm
authors.initials: JH
authors.lastname: van Waesberghe
authors.forename: T M
authors.initials: TM
authors.lastname: Starink
authors.forename: M A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: J J P
authors.initials: JJ
authors.lastname: Gille
authors.forename: F H
authors.initials: FH
authors.lastname: Menko
mesh_terms: D000328:Adult; D000368:Aged; D058249:Birt-Hogg-Dube Syndrome / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011030:Pneumothorax / Q000150:complications / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins