Update of penetrance estimates in Birt-Hogg-Dubé syndrome

Abstract

BackgroundBirt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in theFLCNgene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series.MethodsA comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants inFLCN. Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers ofFLCNpathogenic variants.ResultsOur final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of theFLCNvariant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers.ConclusionsThese updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma

“…So far, we have experienced only one BHD-associated oncocytoma and hence, the frequency of oncocytoma in BHD-associated renal tumours in our cohort is relatively low compared to that in other cohorts. 16 , 44 Although a genotype–phenotype correlation has not been investigated in BHD syndrome, it is urgent to interrogate the elements that possibly affect histological variations across the cohorts.…”

Hereditary Renal Cancer Syndromes

“…1:500,000 (worldwide) [31] 1:176,366 (South Korea) [32] 1:3265 (Sweden) [33] 1:3234 (Pennsylvania, USA) [34] 67% [35]; 80-85% [35] 0.3-1.6%: 0.3% [11,13]; 0.4% [13]; 0.5% [10]; 1.2% [8]; 1.6% [14] RCCs: 19-21%; spontaneous pneumothorax/multiple bilateral pleural/ subpleural cysts: 82-87%; skin lesions (fibrofolliculomas, acrochordons, angiofibromas): 78-87%; colonic polyps: 21-32% [36].…”

“…Population-based study [36]: cystic lung disease: 65.7%; pneumothorax: 17.1%; skin lesions: 8.6%; RCCs: 2.9%…”

Recommendations on scuba diving in Birt-Hogg-Dubé syndrome

“…BHD is characterized by benign skin lesions (fibrofolliculomas) and an increased risk of renal cell carcinoma, pulmonary cystic lesions, and pneumothorax. In 87% of patients with BHD pulmonary involvement consisting of lung cysts and/or pneumothorax is reported [ 9 ]. Of note, recurrent pneumothorax has also been reported in patients with BHD in the absence of detectable lung cysts [ 9 , 10 ].…”

“…In 87% of patients with BHD pulmonary involvement consisting of lung cysts and/or pneumothorax is reported [ 9 ]. Of note, recurrent pneumothorax has also been reported in patients with BHD in the absence of detectable lung cysts [ 9 , 10 ]. We reported the outcomes of extensive clinical and genetic evaluation in two disorders partially overlapping with BHD, familial multiple discoid fibromas and familial lipomatosis associated with PRDM10 [ 11–13 ].…”