Update of penetrance estimates in Birt-Hogg-Dubé syndrome

Fiona Jane Bruinsma; James G. Dowty; Aung Ko Win; Laura C. Goddard; Prachi Agrawal; Domenico Attina'; Nabil Bissada; Monica De Luise; Daniel B. Eisen; Mitsuko Furuya; Giuseppe Gasparre; Maurizio Genuardi; Anne-Marie Gerdes; Thomas Van Overeem Hansen; Arjan C. Houweling; Paul Christiaan Johannesma; André Lencastre; Derek Lim; Noralane M Lindor; Valentina Luzzi; Maeve Lynch; Antonella Maffé; Fred H. Menko; Guido Michels; Jose S. Pulido; Jay H. Ryu; Elke C. Sattler; Ortrud K. Steinlein; Sara Tomassetti; Kathy Tucker; Daniela Turchetti; Irma van de Beek; Lore van Riel; Maurice van Steensel; Thierry Zenone; Maurizo Zompatori; Jennifer Walsh; Davide Bondavalli; Eamonn R. Maher; Ingrid M. Winship

doi:10.1136/jmg-2022-109104

Update of penetrance estimates in Birt-Hogg-Dubé syndrome

Fiona Jane Bruinsma, James G. Dowty, Aung Ko Win, Laura C. Goddard, Prachi Agrawal, Domenico Attina', Nabil Bissada, Monica De Luise, Daniel B. Eisen, Mitsuko Furuya, Giuseppe Gasparre, Maurizio Genuardi, Anne-Marie Gerdes, Thomas Van Overeem Hansen, Arjan C. Houweling, Paul Christiaan Johannesma, André Lencastre, Derek Lim, Noralane M Lindor, Valentina LuzziMaeve Lynch, Antonella Maffé, Fred H. Menko, Guido Michels, Jose S. Pulido, Jay H. Ryu, Elke C. Sattler, Ortrud K. Steinlein, Sara Tomassetti, Kathy Tucker, Daniela Turchetti, Irma van de Beek, Lore van Riel, Maurice van Steensel, Thierry Zenone, Maurizo Zompatori, Jennifer Walsh, Davide Bondavalli, Eamonn R. Maher, Ingrid M. Winship

Aston Medical School

Research output: Contribution to journal › Review article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	317-326
Number of pages	10
Journal	Journal of Medical Genetics
Volume	60
Issue number	4
Early online date	27 Feb 2023
DOIs	https://doi.org/10.1136/jmg-2022-109104
Publication status	Published - 20 Mar 2023

Keywords

Gene Expression
Genetic Predisposition to Disease
Genetic Research
Human Genetics

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10.1136/jmg-2022-109104

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Bruinsma, F. J., Dowty, J. G., Win, A. K., Goddard, L. C., Agrawal, P., Attina', D., Bissada, N., De Luise, M., Eisen, D. B., Furuya, M., Gasparre, G., Genuardi, M., Gerdes, A.-M., Hansen, T. V. O., Houweling, A. C., Johannesma, P. C., Lencastre, A., Lim, D., Lindor, N. M., ... Winship, I. M. (2023). Update of penetrance estimates in Birt-Hogg-Dubé syndrome. Journal of Medical Genetics, 60(4), 317-326. https://doi.org/10.1136/jmg-2022-109104

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title = "Update of penetrance estimates in Birt-Hogg-Dub{\'e} syndrome",

abstract = "BACKGROUND: Birt-Hogg-Dub{\'e} (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.",

keywords = "Gene Expression, Genetic Predisposition to Disease, Genetic Research, Human Genetics",

author = "Bruinsma, {Fiona Jane} and Dowty, {James G.} and Win, {Aung Ko} and Goddard, {Laura C.} and Prachi Agrawal and Domenico Attina' and Nabil Bissada and {De Luise}, Monica and Eisen, {Daniel B.} and Mitsuko Furuya and Giuseppe Gasparre and Maurizio Genuardi and Anne-Marie Gerdes and Hansen, {Thomas Van Overeem} and Houweling, {Arjan C.} and Johannesma, {Paul Christiaan} and Andr{\'e} Lencastre and Derek Lim and Lindor, {Noralane M} and Valentina Luzzi and Maeve Lynch and Antonella Maff{\'e} and Menko, {Fred H.} and Guido Michels and Pulido, {Jose S.} and Ryu, {Jay H.} and Sattler, {Elke C.} and Steinlein, {Ortrud K.} and Sara Tomassetti and Kathy Tucker and Daniela Turchetti and {van de Beek}, Irma and {van Riel}, Lore and {van Steensel}, Maurice and Thierry Zenone and Maurizo Zompatori and Jennifer Walsh and Davide Bondavalli and Maher, {Eamonn R.} and Winship, {Ingrid M.}",

year = "2023",

month = mar,

day = "20",

doi = "10.1136/jmg-2022-109104",

language = "English",

volume = "60",

pages = "317--326",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "4",

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Bruinsma, FJ, Dowty, JG, Win, AK, Goddard, LC, Agrawal, P, Attina', D, Bissada, N, De Luise, M, Eisen, DB, Furuya, M, Gasparre, G, Genuardi, M, Gerdes, A-M, Hansen, TVO, Houweling, AC, Johannesma, PC, Lencastre, A, Lim, D, Lindor, NM, Luzzi, V, Lynch, M, Maffé, A, Menko, FH, Michels, G, Pulido, JS, Ryu, JH, Sattler, EC, Steinlein, OK, Tomassetti, S, Tucker, K, Turchetti, D, van de Beek, I, van Riel, L, van Steensel, M, Zenone, T, Zompatori, M, Walsh, J, Bondavalli, D, Maher, ER & Winship, IM 2023, 'Update of penetrance estimates in Birt-Hogg-Dubé syndrome', Journal of Medical Genetics, vol. 60, no. 4, pp. 317-326. https://doi.org/10.1136/jmg-2022-109104

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.

PY - 2023/3/20

Y1 - 2023/3/20

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

UR - https://jmg.bmj.com/content/60/4/317

UR - http://www.scopus.com/inward/record.url?scp=85150751788&partnerID=8YFLogxK

U2 - 10.1136/jmg-2022-109104

DO - 10.1136/jmg-2022-109104

M3 - Review article

C2 - 36849229

SN - 0022-2593

VL - 60

SP - 317

EP - 326

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 4

ER -

Update of penetrance estimates in Birt-Hogg-Dubé syndrome

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