Birt-Hogg-Dubé syndrome encountered at rare lung disease clinic in Anhui province, China

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Abstract

Background

Diagnosis of rare diseases remains a challenge in China. We describe our experience with Birt-Hogg-Dubé syndrome (BHDS) encountered at a Rare Lung Disease Clinic recently established in China.

Methods

After the first patient with BHDS was recognized in 2017, a Rare Lung Disease Clinic with a multidisciplinary team of specialists was established. We retrospectively analyzed the data of consecutive patients with BHDS encountered from inception to December 2021.

Results

There were 1, 1, 15, 12 and 21 cases with BHDS diagnosed from year 2017 to 2021, respectively. All 50 patients (34 women) were of Han race with a mean age of 47.4 years. The common manifestations were pulmonary cysts (98%), pneumothorax (54%) and skin lesions (68%). Renal cancer was detected in two patients and renal angiomyolipoma in four other patients. The main presentations leading to diagnosis were pneumothorax (42%), family screening (36%), and lung cysts identified on radiologic imaging (20%). The average delay in diagnosis was 8.3 years, and 4.7 years in patients with only pulmonary cysts. The most frequent pathogenic variant was c.1285del/dup on exon 11 (23%) among 44 patients confirmed by genetic testing. Renal cancer has not been found on follow-up surveillance thus far.

Conclusions

Increasing number of patients with BHDS are being recognized in China, facilitated by establishment of a Rare Lung Disease Clinic. Pulmonary cysts and pneumothorax were commonly encountered features, but skin lesions appeared to be more prevalent in Chinese subjects than previously reported in other Asian countries.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13023-022-02362-1.

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Most cited references 34

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Birt-Hogg-Dubé syndrome: diagnosis and management.

Fred H Menko, Maurice Van Steensel, Sophie Giraud … (2009)

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition characterised clinically by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cancer. The condition is caused by germline mutations in the FLCN gene, which encodes folliculin; the function of this protein is largely unknown, although FLCN has been linked to the mTOR pathway. The availability of DNA-based diagnosis has allowed insight into the great variation in expression of FLCN, both within and between families. Patients can present with skin signs and also with pneumothorax or renal cancer. Preventive measures are aimed mainly at early diagnosis and treatment of renal cancer. This Review gives an overview of current diagnosis and management of BHD.

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Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.

Arthur R. Birt (1977)

In a sibship of nine, six members had hereditary medullary carcinoma of the thyroid. Two of those with thyroid neoplasms and two without had numerous small papular skin lesions. These proved to be a type of pilar tumor that we named fibrofolliculoma. Further investigation of the total kindred of 70 showed no other evidence of thyroid neoplasm. Skin tumors only appeared after the age of 25 years. Fifteen of 37 members older than the age of 25 years exhibited the typical skin lesions. Obviously, the original sibship was the repository of two dominantly inherited traits. The fibrofolliculoma is characterized by abnormal hair follicles with epithelial strands extending out from the infundibulum of the hair follicle into a hyperplastic mantle of specialized firbrous tissue. Associated skin lesions in this kindred were trichodiscomas and acrochordons.

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BHD mutations, clinical and molecular genetic investigations of Birt–Hogg–Dubé syndrome: a new series of 50 families and a review of published reports

J R Toro, M-H Wei, G Glenn … (2008)

Background: Birt–Hogg–Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations. Objective: To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS. Methods: Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences. Results: The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with BHD germline mutation is discussed. Conclusion: BHDS is characterised by a spectrum of mutations, and clinical heterogeneity both among and within families.

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Author and article information

Contributors

Xiaowen Hu:

ORCID: http://orcid.org/0000-0002-3727-6049

hu.xiaowen@hotmail.com

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 16 May 2022

Publication date PMC-release: 16 May 2022

Publication date Collection: 2022

Volume: 17

Electronic Location Identifier: 203

Affiliations

[1 ]GRID grid.59053.3a, ISNI 0000000121679639, Division of Life Sciences and Medicine, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of USTC, , University of Science and Technology of China, ; Hefei, 230001 Anhui China

[2 ]GRID grid.443626.1, ISNI 0000 0004 1798 4069, WanNan Medical College, ; Wuhu, Anhui China

[3 ]GRID grid.59053.3a, ISNI 0000000121679639, Division of Life Sciences and Medicine, Department of Dermatology, The First Affiliated Hospital of USTC, , University of Science and Technology of China, ; Hefei, Anhui China

[4 ]GRID grid.252957.e, ISNI 0000 0001 1484 5512, BengBu Medical College, ; Bengbu, Anhui China

[5 ]GRID grid.59053.3a, ISNI 0000000121679639, Division of Life Sciences and Medicine, Department of Thoracic Surgery, The First Affiliated Hospital of USTC, , University of Science and Technology of China, ; Hefei, Anhui China

[6 ]GRID grid.59053.3a, ISNI 0000000121679639, Division of Life Sciences and Medicine, Department of Pathology, The First Affiliated Hospital of USTC, , University of Science and Technology of China, ; Hefei, Anhui China

[7 ]GRID grid.59053.3a, ISNI 0000000121679639, Division of Life Sciences and Medicine, Department of Urology, , The First Affiliated Hospital of USTC, University of Science and Technology of China, ; Hefei, Anhui China

[8 ]GRID grid.59053.3a, ISNI 0000000121679639, Division of Life Sciences and Medicine, Department of Radiology, The First Affiliated Hospital of USTC, , University of Science and Technology of China, ; Hefei, Anhui China

[9 ]GRID grid.186775.a, ISNI 0000 0000 9490 772X, School of Basic Medicine, , Anhui Medical University, ; Hefei, Anhui China

[10 ]GRID grid.41156.37, ISNI 0000 0001 2314 964X, Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, , Nanjing University, ; Nanjing, Jiangsu China

[11 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Division of Pulmonary and Critical Care Medicine, , Mayo Clinic, ; Rochester, MN USA

Author information

Xiaowen Hu http://orcid.org/0000-0002-3727-6049

Article

Publisher ID: 2362

DOI: 10.1186/s13023-022-02362-1

PMC ID: 9112470

PubMed ID: 35578266

SO-VID: b7f4d6d3-8a40-49cb-8b22-d51fe1ac1b65

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 2 February 2022

Date accepted : 8 May 2022

Funding

Funded by: Health Commission of Anhui Province

Award ID: 2021szdzk05

Award Recipient : Xiaowen Hu

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: birt-hogg-dubé syndrome,flcn gene,pneumothorax

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: birt-hogg-dubé syndrome, flcn gene, pneumothorax

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Birt-Hogg-Dubé syndrome encountered at rare lung disease clinic in Anhui province, China

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Abstract

Background

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Conclusions

Supplementary Information

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Most cited references 34

Birt-Hogg-Dubé syndrome: diagnosis and management.

Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.

BHD mutations, clinical and molecular genetic investigations of Birt–Hogg–Dubé syndrome: a new series of 50 families and a review of published reports

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