TY - JOUR

T1 - Update of penetrance estimates in Birt-Hogg-Dubé syndrome

AU - Bruinsma, Fiona Jane

AU - Dowty, James G.

AU - Win, Aung Ko

AU - Goddard, Laura C.

AU - Agrawal, Prachi

AU - Attina', Domenico

AU - Bissada, Nabil

AU - De Luise, Monica

AU - Eisen, Daniel B.

AU - Furuya, Mitsuko

AU - Gasparre, Giuseppe

AU - Genuardi, Maurizio

AU - Gerdes, Anne Marie

AU - Hansen, Thomas Van Overeem

AU - Houweling, Arjan C.

AU - Johannesma, Paul Christiaan

AU - Lencastre, André

AU - Lim, Derek

AU - Lindor, Noralane M.

AU - Luzzi, Valentina

AU - Lynch, Maeve

AU - Maffé, Antonella

AU - Menko, Fred H.

AU - Michels, Guido

AU - Pulido, Jose S.

AU - Ryu, Jay H.

AU - Sattler, Elke C.

AU - Steinlein, Ortrud K.

AU - Tomassetti, Sara

AU - Tucker, Kathy

AU - Turchetti, Daniela

AU - Van De Beek, Irma

AU - Van Riel, Lore

AU - Van Steensel, Maurice

AU - Zenone, Thierry

AU - Zompatori, Maurizo

AU - Walsh, Jennifer

AU - Bondavalli, Davide

AU - Maher, Eamonn R.

AU - Winship, Ingrid M.

N1 - Publisher Copyright: © 2023 BMJ Publishing Group. All rights reserved.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Gene Expression

KW - Genetic Predisposition to Disease

KW - Genetic Research

KW - Human Genetics

U2 - 10.1136/jmg-2022-109104

DO - 10.1136/jmg-2022-109104

M3 - Review

C2 - 36849229

AN - SCOPUS:85150751788

VL - 60

SP - 317

EP - 326

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 4

ER -