The clinical characteristics of East Asian patients with Birt-Hogg-Dubé syndrome

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Abstract

Background

Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant disease that has been characterized by skin lesions, multiple pulmonary cysts, spontaneous pneumothorax, and renal tumors, but the patients in Asian countries may show fewer symptoms. We aimed to explore and summarize the clinical features of BHD patients in East Asia to facilitate early diagnosis and timely interventions.

Methods

We collected and analyzed the clinical data of patients diagnosed with BHD in our hospital by reviewing medical records. We performed a systematic literature search regarding the presenting clinical features in BHD patients from China, Japan, and Korea and then reviewed the publications that were identified.

Results

In our hospital, 10 patients were diagnosed with BHD from April 2015 to September 2019. After reviewing the literature, we recruited 38 articles, including 12, 20, and 6 reports from China, Japan, and Korea, respectively. A total of 166 patients were included in this study, and 100 of them (60.2%) were females. Multiple pulmonary cysts were present in 145 patients (87.3%), and 124 patients (74.7%) had a history of pneumothorax on at least one occasion. Skin biopsy confirmed fibrofolliculomas (FFs) alone in 22 patients (13.3%), trichodiscomas (TDs) alone in 3 patients (1.8%), and both FFs and TDs in 7 patients (4.2%). Renal carcinoma only occurred in 12 (7.2%) patients. The most frequent genetic mutations in East Asian patients were c.1285delC on exon 11 (18.4%), c.1285dupC on exon 11 (18.4%), and c.1347_1353dupCCACCCT on exon 12 (8.2%).

Conclusions

Our findings suggested that pulmonary cysts are the most frequent radiological findings, and pneumothorax is the most common symptom in East Asian patients with BHD, and that skin lesions and kidney involvement are less frequent. To make an early diagnosis and minimize the severity of complications, careful observation, and timely genetic examination of the FLCN gene is essential.

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Most cited references 59

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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

Journal

Journal ID (nlm-ta): Ann Transl Med

Journal ID (iso-abbrev): Ann Transl Med

Journal ID (publisher-id): ATM

Title: Annals of Translational Medicine

Publisher: AME Publishing Company

ISSN (Print): 2305-5839

ISSN (Electronic): 2305-5847

Publication date (Print and electronic): November 2020

Publication date (Print): November 2020

Volume: 8

Issue: 21

Electronic Location Identifier: 1436

Affiliations

[1 ]Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central-South University , Changsha, China;

[2 ]Research Unit of Respiratory Disease, Central-South University , Changsha, China;

[3 ] The Respiratory Disease Diagnosis and Treatment Center of Hunan Province , Changsha, China

Author notes

Contributions: (I) Conception and design: H Peng, T Guo; (II) Administrative support: P Chen, H Peng; (III) Provision of study materials or patients: Q Shen, R Ouyang, M Song, D Zong, Z Shi, Y Long; (IV) Collection and assembly of data: T Guo, Q Shen; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Hong Peng, MD, PhD. Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central-South University, NO. 139 Renmin Middle Road, Changsha 410011, China. Email: penghong66@ 123456csu.edu.cn .

Article

Accession ID: PMC7723594 Pmcid ID: PMC7723594 Pmc-uid ID: 7723594 Publisher ID: atm-08-21-1436

DOI: 10.21037/atm-20-1129

PMC ID: 7723594

PubMed ID: 33313181

SO-VID: 3f7bc001-817b-4494-9c4f-431d4d6cb255

History

Date received : 31 January 2020

Date accepted : 28 August 2020

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The clinical characteristics of East Asian patients with Birt-Hogg-Dubé syndrome

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Most cited references 59

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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Cited by 10

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