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.Conclusion: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.

Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax

“…Pneumothorax was observed in 5 out of 17 (29.4%) members who carried a mutation in this family, which was similar to a prevalence of 29% in a previous report (21). However, according to Jodie et al, the bullous lung changes observed on chest CT scan should be considered as the pulmonary manifestation of this syndrome (15).…”

Review of renal tumors associated with Birt-Hogg-Dubé syndrome with focus on clinical and pathobiological aspects

“…1B). Papillary RCC with oncocytic change, clear cell RCC with focal papillary structures, RCC with a mixture of eosinophilic and focal clear cells with tubulopapillary architecture, sarcomatoid RCC and unclassified RCC have been described [17,29,31,36,37]. The association with renal angiomyolipoma has also been reported [38,39].…”

“…A variety of histological subtypes including hybrid oncocytic tumor, chromophobe RCC, oncocytoma, papillary RCC and clear cell RCC have been observed [9,17,19,20,22,30,[33][34][35]. Hybrid oncocytic tumors have both areas reminiscent of chromophobe RCC having a well-defined cell border, pyknotic nuclei and perinuclear halo and oncocytoma showing ill-defined cell borders, finely granular eosinophilic cytoplasm and round nuclei [18] (Fig.…”

“…There is a male predominance in renal tumors associated with BHDS [18]. The estimated penetrance of renal cancer in FLCN gene mutation carriers in BHDS families is 16% at 70 years of age [17]. The risk of developing renal tumors in BHDS-affected patients is approximately 7 times higher than in non-BHDS-affected patients [19].…”

“…Renal tumors associated with BHDS are diagnosed at the age ranging from 20 to 75 years, but often occur before 50 years of age [3,5,[15][16][17]. Renal tumors occur in 25-35% of patients with BHDS [14,18].…”