Estimating the risk of pneumothorax and renal cell carcinoma in BHD patients

Many studies into BHD syndrome have investigated the prevalence of pneumothorax and renal cell carcinoma amongst FLCN mutation carriers. Previous estimations of the RCC risk have varied from 6.5% to 34% (Toro et al., 2008), and for pneumothorax, from 24% to 38% (Schmidt et al., 2005; Toro et al., 2007; Toro et al., 2008). This variation is likely to be due to ascertainment bias. Recently, a study by Houweling et al. (2011) investigated 115 FLCN mutation carriers from 35 families to reassess the risk of RCC and pneumothorax in BHD syndrome. The study also evaluated the histological subtypes of renal cancer commonly found in BHD patients. The majority of patients were referred by dermatologists and so it is important to remember that this study may also have an ascertainment bias.

From the 115 FLCN mutation carriers assessed in this study, 28 (24%) had a history of pneumothorax, 8 of which were recurrent. The mean age of the first pneumothorax was found to be 36 (range 18 – 74). CT examination of 12 FLCN mutation carriers showed that 5 patients (42%) had multiple lung cysts. After incorporating data on relatives who did not undergo DNA testing for FLCN mutations, the estimated prevalence for the first episode of spontaneous pneumothorax was found to be 29% at 70 years.

The same analysis was carried out to determine the risk of RCC amongst BHD patients. 14 out of the 115 FLCN mutation carriers (12%) had RCC, 5 of which had metastasised. Three BHD patients had multiple cases of renal cancer. Taking all the data together, including the non-tested BHD family members, the prevalence for renal cancer was 16% at age 70.

Previous reports found that the most prevalent RCC histology identified in BHD syndrome was a hybrid chromophobe and oncocytic tumour (Pavlovich et al., 2002). However, several other histologies have also been identified. The histology of the renal tumours in this cohort was determined and it was found that the majority of tumours had characteristics of both chromophobe and clear cell carcinoma. The tumours also resembled those seen in sporadic RCC. Knowing the histological pattern expected in BHD tumours could aid early diagnosis.

Determining the prevalence of pneumothorax and RCC risk in BHD syndrome is important for planning the correct surveillance programme for FLCN mutation carriers and their families. The guidelines proposed by Menko et al. (2009) suggest beginning renal cancer surveillance for BHD patients at age 20 and performing annual MRI scans. Although the reported prevalence in this study for both RCC and pneumothorax is lower than that in some of the previous studies, the need for surveillance and an awareness of BHD symptoms is as important as ever.


  • Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, & Linehan WM (2005). Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. American journal of human genetics, 76 (6), 1023-33 PMID: 15852235
  • Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, Wei MH, Schmidt LS, Davis L, Zbar B, Choyke P, Steinberg SM, Nguyen DM, & Linehan WM (2007). Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. American journal of respiratory and critical care medicine, 175 (10), 1044-53 PMID: 17322109
  • Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, & Linehan WM (2008). BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. Journal of medical genetics, 45 (6), 321-31 PMID: 18234728
  • Houweling AC, Gijezen LM, Jonker MA, van Doorn MB, Oldenburg RA, van Spaendonck-Zwarts KY, Leter EM, van Os TA, van Grieken NC, Jaspars EH, de Jong MM, Bongers EM, Johannesma PC, Postmus PE, van Moorselaar RJ, van Waesberghe JH, Starink TM, van Steensel MA, Gille JJ, & Menko FH (2011). Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. British journal of cancer, 105 (12), 1912-9 PMID: 22146830
  • Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, & Merino MJ (2002). Renal tumors in the Birt-Hogg-Dubé syndrome. The American journal of surgical pathology, 26 (12), 1542-52 PMID: 12459621
  • Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER, & European BHD Consortium (2009). Birt-Hogg-Dubé syndrome: diagnosis and management. The lancet oncology, 10 (12), 1199-206 PMID: 19959076

2 thoughts on “Estimating the risk of pneumothorax and renal cell carcinoma in BHD patients

Leave a Reply