Birt–Hogg–Dubé syndrome in an Indonesian patientwith folliculin gene mutationWiwien Heru Wiyono, Fariz Nurwidya, Hario Baskoro & Andika Chandra Putra

Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.

KeywordsBirt–Hogg–Dubé syndrome, FLCN gene mutation,multiple lung cysts.

CorrespondenceFariz Nurwidya, Department of Pulmonology andRespiratory Medicine, Faculty of Medicine, Universi-tas Indonesia, Persahabatan Hospital, Jalan Persaha-batan Raya No. 1, Rawamangun Jakarta 13230,Indonesia. E-mail: fariz.nurwidya@gmail.com

Received: 27 May 2016; Revised: 23 July 2016;26 August 2016; 17 September 2016 and1 October 2016; Accepted: 3 October 2016;Associate Editor: Helen Davies.

Respirology Case Reports, 4 (6), 2016, e00199

doi: 10.1002/rcr2.199

Abstract

Birt–Hogg–Dubé (BHD) syndrome is a rare autosomal dominant disorderthat affects the skin, kidney, and lungs. Affected individuals have anincreased risk of developing multiple cysts in the lungs and a spontane-ous pneumothorax. Germline mutations in the folliculin (FLCN) genehave been confirmed as the aetiology of BHD syndrome. A 51-year-oldIndonesian female presented with recurrent spontaneous pneumothorax,multiple cysts in both lungs, and a renal cyst on magnetic resonance ima-ging (MRI). Blood sampling was performed to extract genomic DNAfrom peripheral blood leucocytes. We identified an aberrant band in theDNA fragment derived from FLCN exon 6. Moreover, direct sequencingof FLCN exon 6 by denaturing high-performance liquid chromatography(DHPLC) showed a pathogenic mutation, which caused premature termi-nation of folliculin protein translation. This is the first reported case ofBHD syndrome in an Indonesian patient confirmed by detection of aFLCN exon 6 mutation.

Introduction

Birt–Hogg–Dubé syndrome (BHDS) is a rare hereditarydisease that presents with multiple pulmonary cysts,fibrofolliculomas, and recurrent pneumothorax. It wasfirst described in 1977 as a familial dermatologic disor-der by Birt and colleagues [1]. The prevalence of BHDSis difficult to determine because this disease is very rare.BHDS is predicted to be responsible for 5–10% ofpatients with primary spontaneous pneumothorax [2].BHDS is caused by germline, predominantly truncatingmutations in the folliculin (FLCN) gene located onchromosome 17, which encodes a highly conservedtumour suppressor protein folliculin [2]. FLCN genemutations were first discovered by Nickerson and col-leagues in 2002 and have provided the basis for ourunderstanding of the role of FLCN in pathways com-mon to skin, lung, and kidney development [2]. InAsia, BHDS has been identified in several countries;however, there have been no reports of BHDS in aSoutheast Asian patient.

Case Report

A 51-year-old Indonesian female, with a medical history ofmultiple lung cysts, presented to our hospital complainingof shortness of breath but without a cough, chest pain, orfever. A computed tomography (CT) scan of her chestdemonstrated multiple cysts on both lungs as previouslynoted (Fig. 1A). Her family history revealed that hermother had a history of renal tumour, although the patientwas not sure whether it was malignant or not. We per-formed magnetic resonance imaging (MRI) of her abdomenand a renal cyst was noted (Fig. 1B). The combination ofpulmonary and renal cysts raised the possibility of BHDS.This clinical suspicion was confirmed on folliculin (FLCN)gene mutation analysis that was carried out on DNA iso-lated from peripheral blood leucocytes. Each exon of theFLCN gene was amplified by polymerase chain reaction(PCR) and subjected to denaturing high-performance liq-uid chromatography (DHPLC). This detected an aberrantband in the DNA fragment derived from exon 6. Directsequencing identified a pathogenic mutation c.601C > T

© 2016 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltdon behalf of The Asian Pacific Society of RespirologyThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided theoriginal work is properly cited.

2016 | Vol. 4 | Iss. 6 | e00199Page 1

Official Case Reports Journal of the Asian Pacific Society of Respirology

Respirology Case Reports

(see sequence chromatogram; Fig. 2). This nonsense muta-tion triggers a premature stop codon at Q201 and early ter-mination of protein translation. Family members of thepatient declined screening.

Discussion

This was a rare case of multiple cysts in the lung accompa-nied by kidney cyst in a patient with a maternal history ofa renal tumour. Confirmation of BHDS was provided byFLCN gene mutation analysis. The availability of DNA-based diagnosis has allowed insight into the great variationin clinical manifestation of BHDS. For example, somepatients with a specific mutation in the FLCN gene mayhave a higher risk of recurrent spontaneous pneumothorax[3], although all BHDS patients have a heightened risk. Inaddition to cutaneous fibrofolliculomas, pulmonary cystsand repeated episodes of pneumothorax are the key diag-nostic features of BHDS. About 80% of BHDS patients

have multiple pulmonary cysts on their CT scans. Theseare typically small thin-walled cysts, are adjacent to the fis-sures, often involve the lower lobes, are prone to rupture,and consequently a pneumothorax may be the initial pres-entation of this disease.Multiple biopsy-proven fibrofolliculomas are diagnostic

for BHDS and occur in >80% of BHDS-affected indivi-duals. However, Tomassetti et al. [3] reported BHDS-affected patients without skin papules, and fewer than 50%of a cohort of Japanese Asian FLCN mutation carriers pre-sented with skin papules, suggesting that lung and kidneylesions may be more informative than fibrofolliculomas asthe diagnostic criteria for BHDS in the Japanese Asianpopulation [4].Renal tumours, most commonly chromophobe or

hybrid oncocytic renal tumours, may develop in up toone-third of BHDS-affected individuals [5]. Of note, ourpatient reported a maternal family history of renal tumour,although an abdominal MRI revealed only a single renalcyst in our patient, which has been infrequently reportedin BHDS. It is unknown whether this benign renal cyst willprogress to a renal tumour in the future.In accordance with recently published findings, our

results help to raise further awareness about BHDS [2]. Tothe best of our knowledge, this report presents the firstpublished case of BHDS in a patient from Southeast Asiathat was confirmed by a FLCN exon 6 nonsense mutationpredicted to truncate the folliculin protein. Given that thispatient presented only with pulmonary manifestationswithout renal tumour or skin papules, this case report

Figure 1. (A) Thoracic computed tomography of the patient showedmultiple bilateral pulmonary cysts. (B) Abdominal magnetic resonanceimaging revealed a renal cyst (white arrow).

Pat

ient

Con

trol

196lle

A T C A A A A A A A AT T T TC C C C C C C CG G G GG G G G G G

lle Asp Glu Leu AlaGln Gly Lys LysLeu197 198 199 200 201 202 203 204 205 206

196lle

A T C A A A A A A A AT T T TC C C C C C C CG G G G G G G G G G

A T C A A A A A A A AT T T TC C C T C C C CG G G G G G G G G G

lle Asp Glu Leu AlaGln Gly Lys LysLeu197 198 199 200 201

201Stop

exon 6 c.601C>T, Q201*(CAG→TAG)

202 203 204 205 206

Figure 2. Sequence chromatogram of the FLCN gene showed a muta-tion in exon 6.

BHD syndrome in an Indonesian patient W.H. Wiyono et al.

2 © 2016 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltdon behalf of The Asian Pacific Society of Respirology

should raise awareness among pulmonologists in SoutheastAsia to consider genetic testing for BHDS in a patient whopresents with multiple lung cysts with or without historyof pneumothorax, especially when skin papules and/orrenal tumours are also present in the patient or his/herfamily history. Conversely, BHDS may be suspected in apatient who presents with bilateral multifocal renaltumours with chromophobe or hybrid oncocytic histology,and screening for pulmonary or cutaneous manifestationsmay be recommended. Owing to the increased risk of renalcancer in BHDS patients, individuals with a pathogenicFLCN mutation should undergo periodic screening byabdominal MRI. BHDS patients presenting with lung cystsshould be made aware of the risk of developing a sponta-neous pneumothorax and instructed to avoid activities thatwould suddenly change intra-thoracic pressure (i.e., scubadiving). Pleurodesis may be considered in BHDS patientswith previous spontaneous pneumothorax in order toavoid recurrence.

Disclosure Statements

No conflict of interest declared.Appropriate written informed consent was obtained forpublication of this case report and accompanying images.

Acknowledgements

We appreciate the advice, expertise, and technical supportof Dr. Kuniaki Seyama, Dr. Hiroki Ebana, Ms. EtsukoKobayashi, Dr. Tadashi Sato, Dr. Fumiyuki Takahashi, andProfessor Kazuhisa Takahashi, Department of RespiratoryMedicine, Juntendo University Graduate School ofMedicine.

References

1. Birt AR, Hogg GR, and Dube WJ 1977. Hereditary multiplefibrofolliculomas with trichodiscomas and acrochordons.Arch. Dermatol. 113:1674–1677.

2. Gupta N, Sunwoo BY, and Kotloff RM 2016. Birt–Hogg–Dube syndrome. Clin. Chest Med. 37:475–486.

3. Tomassetti S, Carloni A, Chilosi M, et al. 2011. Pulmonaryfeatures of Birt–Hogg–Dube syndrome: cystic lesions andpulmonary histiocytoma. Respir. Med. 105:768–774.

4. Furuya M, Yao M, Tanaka R, et al. 2016. Genetic, epidemio-logic and clinicopathologic studies of Japanese Asian patientswith Birt–Hogg–Dube syndrome. Clin. Genet. doi: 10.1111/cge.12807.

5. Schmidt LS, and Linehan WM 2015. Molecular genetics andclinical features of Birt–Hogg–Dube syndrome. Nat. Rev.Urol. 12:558–569.

W.H. Wiyono et al. BHD syndrome in an Indonesian patient

© 2016 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltdon behalf of The Asian Pacific Society of Respirology

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