When to test for Birt-Hogg-Dubé Syndrome? UK national data

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Background: Birt-Hogg-Dubé syndrome (BHD) is the commonest monogenic cause of pneumothorax. Caused by pathogenic variants within FLCN it can manifest as pneumothorax, pulmonary cysts, and skin features like fibrofolliculomas. Affected families are at increased risk of renal malignancy and diagnosis permits lifesaving renal surveillance. Our gene panel developed in the 100,000 Genomes Project became the UK genetic test for Familial Pneumothorax: the R190 panel. Testing criteria were initially: a history of spontaneous pneumothorax and a first-degree relative with pneumothorax. However, not all suspected cases meet these criteria. Methods: We analysed national and regional data to assess the predictive value of these criteria for diagnosis of BHD using data from (i) the Rare Disease Collaborative Network (RDCN) for Familial Pneumothorax (n=77 patients); (ii) North East and Yorkshire Genomic Laboratory Hub (GLH, n=68 patients); (iii) Cambridge University Hospitals (n=53 patients). Results: GLH referral for testing had a 24% (16/68) FLCN positivity; fraction positivity increased to 36% (9/25) with clinical suspicion of “syndromic diagnosis” RDCN MDT recommendation for testing had a 38% (8/21) FLCN-positivity CUH cohort: 20% (10/51) confirmed FLCN positivity, with higher positivity (33%, 10/30) in those with pulmonary cysts; 20% of those with FLCN pathogenic variants had bibasal pulmonary cysts but no pneumothorax history Conclusion: Our data support extending FLCN gene testing to individuals with characteristic lung cysts alone. Expanding FLCN gene testing will enable earlier diagnosis, facilitating family surveillance for renal malignancies and personalised care.

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