Luzzi, Valentina

Background Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. 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. Methods A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN . Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants. Results Our 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 the FLCN variant 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. Conclusions These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

Abstract Rationale Lung biopsy (LBx) has a relevant role in the prediction of prognosis of interstitial lung diseases (ILDs), but its impact on the clinical management of patients remains unexplored. Objectives This study evaluates whether LBx may change the therapeutic strategy and assesses the effect of diagnostic reclassification after LBx on long-term prognosis. Methods We evaluated the LBx of 426 consecutive patients with ILDs, without a definite usual interstitial pneumonia pattern on high-resolution computed tomographic imaging. A total of 266 patients underwent transbronchial lung cryobiopsy (TBLC), and 160 patients underwent surgical lung biopsy (SLB). The multidisciplinary team (MDT) determined a diagnosis with high or low confidence, and a management strategy, both before and after the LBx data. Results Final MDT diagnoses were 189 idiopathic pulmonary fibrosis (IPF), 143 non-IPF fibrotic ILDs, and 94 nonfibrotic ILDs. LBx data changed the management strategy in 145 cases (34%), with similar results for TBLC and SLB (the treatment strategy changed in 31.5% of TBLC cases, 84/266, P < 0.001, and in 38% of SLB, 61/160, P < 0.001). After LBx, the MDT was less inclined to “wait and see” (from 15% to 4% of cases, P < 0.001) or to prescribe steroids only (from 54% to 37%, P < 0.001) and was more confident to treat with antifibrotics (from 23% to 44%, P < 0.001) or immunosuppressive drugs (from 7% to 14%, P < 0.001). The therapeutic strategy changed in 70% of reclassified cases (60/85) and in 59% of cases in which LBx increased the MDT confidence (84/142). Reclassification significantly impacted the outcome. The cases classified as non-IPF by clinician and radiologist and then reclassified to be IPF after LBx showed a significantly worse survival compared with non-IPF confirmed cases (adjusted hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.75–8.3); P = 0.001. Cases initially classified as IPF and then reclassified as non-IPF after LBx showed a better prognosis compared with IPF confirmed cases (HR, 0.41; 95% CI, 0.18–0.94; P = 0.03). Conclusions Reclassification of cases with LBx data increased diagnostic confidence and changed the therapeutic strategy in one-third of cases. Pathologic reclassification of cases refined prognosis prediction. Patients classified as non-IPF by clinician and radiologist and then reclassified IPF after LBx had worse prognosis compared with the non-IPF confirmed cases.