Birt-Hogg-Dubé综合征外显率估计的更新

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

作者信息

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

机构信息

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, Victoria, Australia.

出版信息

J Med Genet. 2023 Apr;60(4):317-326. doi: 10.1136/jmg-2022-109104. Epub 2023 Feb 27.

DOI:10.1136/jmg-2022-109104

PMID:36849229

Abstract

BACKGROUND

Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the 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 . Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of 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 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.

摘要

背景

Birt-Hogg-Dubé（BHD）综合征是一种罕见的遗传综合征，由该基因的致病性或可能致病性种系变异引起。BHD综合征患者患纤维毛囊瘤、肺囊肿、气胸和肾细胞癌的风险增加。关于是否应将结肠息肉纳入该综合征的诊断标准存在争议。以往的风险评估大多基于小型临床病例系列。

方法

进行了一项全面综述，以确定招募了携带该基因致病性或可能致病性变异的家族的研究。向这些研究索取家系数据并进行汇总。采用分离分析来估计致病性变异携带者出现每种临床表现的累积风险。

结果

我们的最终数据集包含204个家族，这些家族至少有一种BHD临床表现具有参考价值（67个家族有皮肤表现相关信息，63个有肺部表现相关信息，88个有肾癌相关信息，29个有息肉相关信息）。到70岁时，该变异的男性携带者患肾肿瘤的估计风险为19%（95%置信区间为12%至31%），肺部受累的风险为87%（95%置信区间为80%至92%），皮肤病变的风险为87%（95%置信区间为78%至93%）；而女性携带者患肾肿瘤的估计风险为21%（95%置信区间为13%至32%），肺部受累的风险为82%（95%置信区间为73%至88%），皮肤病变的风险为78%（95%置信区间为67%至85%）。70岁时男性携带者患结肠息肉的累积风险为21%（95%置信区间为8%至45%），女性携带者为32%（95%置信区间为16%至53%）。