birt-hogg-dube syndrome. state-of-the-art review with ... · review with emphasis on pulmonary...

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Respiratory Medicine (2014) xx, 1e8

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REVIEW

Birt-Hogg-Dube syndrome. State-of-the-artreview with emphasis on pulmonaryinvolvement

Aline Amaral Dal Sasso a,1, Luciana Camara Belem a,2,Glaucia Zanetti a,3, Carolina Althoff Souza b,4,Dante Luiz Escuissato c,5, Klaus Loureiro Irion d,6,Marcos Duarte Guimaraes e,7, Edson Marchiori a,*

a Federal University of Rio de Janeiro, Rio de Janeiro, Brazilb The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canadac Federal University of Parana, Curitiba, Brazild Liverpool Heart and Chest Hospital and the Royal Liverpool University Hospital NHS Trusts, Liverpool,United Kingdome A.C. Camargo Cancer Center, Sao Paulo, Brazil

Received 22 August 2014; accepted 20 November 2014

KEYWORDSBirt-Hogg-Dube;Imaging;Lung diseases;Computed

Abberivations: BHDS, Birt-Hogg-DubeLAM, lymphangioleiomyomatosis; LCHcomplex.* Corresponding author. Rua Thomaz

fax: þ55(21)26299017.E-mail addresses: aline_sasso@hot

[email protected] ([email protected] (M.D. G1 Rua Figueiredo de Magalhaes, 9502 Avenida Ayrton Senna, 111/405, B3 Rua Coronel Veiga, 733/504. Cent4 Department of Diagnostic Imaging5 R. General Carneiro, 181, CEP 8006 Thomas Drive, Liverpool, United K7 Rua Paulo Orozimbo, 726, Aclimac

Please cite this article in press as: Dinvolvement, Respiratory Medicine (2

http://dx.doi.org/10.1016/j.rmed.2010954-6111/ª 2014 Elsevier Ltd. All rig

Summary

Background: Birt-Hogg-Dube syndrome (BHDS) is a rare, inherited autosomal-dominant disor-der characterized by the development of cutaneous lesions, renal tumors, pulmonary cysts,and spontaneous pneumothorax. The gene responsible for BHDS is located on the short armof chromosome 17 (17p11.2) and codes for the protein folliculin, which is believed to be an

syndrome; CT, computed tomography; FLCN, folliculin; HIF-1a, hypoxia-inducible factor 1-alpha;, Langerhans cell histiocytosis; mTOR, mammalian target of rapamycin; TSC, tuberous sclerosis

Cameron, 438, Valparaiso, CEP 25685.120. Petropolis, Rio de Janeiro, Brazil. Tel.:þ55 (24) 22492777;

mail.com (A.A. Dal Sasso), [email protected] (L.C. Belem), [email protected] (G. Zanetti),Souza), [email protected] (D.L. Escuissato), [email protected] (K.L. Irion),uimaraes), [email protected] (E. Marchiori)./506, Copacabana, CEP: 22031-012, Rio de Janeiro e Brazil. Tel.: þ55(32)91217945.arra da Tijuca, CEP 22793-000, Rio de Janeiro, Brazil. Tel.: þ55(21) 2433 3399.ro, CEP 25655-504, Petropolis, Rio de Janeiro, Brazil. Tel.: þ55(24)22429156., The Ottawa Hospital, 501 Smyth Road, Ottawa, K1H8L6, Canada. Tel.: þ1 613 737 8212.60-900, Curitiba, Parana, Brazil. Tel.: þ55(41)33435514.ingdom, L14 3 PE. Tel.: þ441617679073.ao, CEP 01535-001, Sao Paulo/SP, Brazil. Tel.: þ55(11) 32085327.

al Sasso AA, et al., Birt-Hogg-Dube syndrome. State-of-the-art review with emphasis on pulmonary014), http://dx.doi.org/10.1016/j.rmed.2014.11.008

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2 A.A. Dal Sasso et al.

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tomography

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oncogene suppressor protein.Methods: We reviewed currently published literature on the main characteristics of BHDS.Results: Pulmonary cysts and spontaneous pneumothorax are often the presenting manifesta-tions that lead to a final diagnosis in family members affected by the syndrome.Conclusions: Certain imaging characteristics of pulmonary cysts, including size and location,can suggest the diagnosis of BHDS based on chest computed tomography alone. The mainconcern in patients with BHDS is the increased risk of renal carcinoma. The aim of this reviewis to describe the main pathological, clinical, and imaging aspects of BHDS, ranging from itsgenetic basis to treatment, with emphasis on pulmonary involvement.ª 2014 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Epidemiology and genetic aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Pulmonary manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Cutaneous manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Renal manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Other clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Pulmonary imaging findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Pulmonary function tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Imaging criteria for differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Introduction

Birt-Hogg-Dube syndrome (BHDS) is a rare autosomal-dominant disorder characterized by the development ofcutaneous lesions, renal tumors, pulmonary cysts, causingspontaneous pneumothorax. In 1977, Birt, Hogg, and Dubeinvestigated members of the same family who presentedwith thyroid cancers. They found that some of them hadfibrofollicular skin tumors that occurred in an inheritedautosomal dominant pattern [1e3]. Although the familialdisorder was later named BHDS, the German dermatologistsHornstein and Knickenberg had reported similar inheritedskin tumors 2 years previously [4]. The genetic defectresponsible for BHDS has been mapped to a gene on chro-mosome 17p11.2, which encodes the tumor suppressorprotein folliculin (FLCN) [5e7].

Lung cysts have been described in most (77e89%) pa-tients with BHDS, and the estimated incidence of pneu-mothorax in these patients is 33e38% [2,5e8]. No evidenceof neoplasia, inflammation, or fibrosis has been found inassociation with these lung cysts [9]. Classically describedskin findings consist of the triad of hamartomas of the hairfollicles (fibrofolliculomas), tumors of the hair disk (tri-chodiscomas), and skin tags (acrochordons). Renal tumorswhen present are often multiple and bilateral [1,7,10,11].

al Sasso AA, et al., Birt-Hogg-Dub014), http://dx.doi.org/10.1016/

BHDS is probably underdiagnosed because of the widevariability of its clinical presentation [12]. This review de-scribes the main clinical, pathological, and imaging aspectsof BHDS.

Epidemiology and genetic aspects

BHDS is a rare entity, although its precise prevalence isunknown [8,13,14]. Approximately 200 families with path-ogenic FLCN mutations have been described in the litera-ture [13]. Mutation-prone regions tend to differ betweenaffected Japanese and Western families, which maypartially explain geographic differences in phenotypicpresentation [2,15].

The gene responsible for BHDS, located on the short armof chromosome 17 (17p12q11.2), was first identified in 2001based on a mapping analysis conducted in large familiesaffected by BHDS. The FLCN gene sequence was identifiedand named in 2002. It contains 14 exons, 11 of which codify,transcript mRNA and encodes a 579 aminoacid protein(FLCN) [2,7,13,16,17]. FLCN is expressed in a wide varietyof tissues, including skin, type-1 pneumocytes in the lungs,and distal nephron in the kidneys. The FLCN protein wasfound to be over expressed in proliferating epithelialfibrofolliculomas, but its expression was significantly

e syndrome. State-of-the-art review with emphasis on pulmonaryj.rmed.2014.11.008

Birt-Hogg-Dube syndrome 3

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reduced in renal tumor tissues from patients with BHDS,regardless of histological subtype [5,13,16].

Numerous mutations in the FLCN gene have beendescribed. The most frequent is a hot spot mutation thatoccurs within a polycytosine C8 tract of exon 11 and resultsin FLCN truncation [15,16,18e20]. To date, 142 unique DNAmutations of the FLCN gene have been implicated in thepathogenesis of BHDS [2].

BHD mutations in exon 9 have been associated with morelung cysts than those in other exons [6]. In addition, thesize and volume of the largest lung cyst have been found tobe significantly greater in individuals with BHD mutations inexons 9 and 12 than in those with mutations in other exons[6]. The potential relevance of exon 9 mutations for pre-disposition to cancer in BHDS has also been proposed [7,16].

Pathogenesis

The energy-sensing mammalian target of rapamycin(mTOR) pathway has been implicated in the pathogenesis ofseveral hereditary hamartoma syndromes, including BHDS[18]. FLCN is known to interact with the protein FINP1 andits homolog, FINP2, which in turn interact with 50 adenosinemonophosphateeactivated protein kinase, a key moleculethat negatively regulates mTOR activity. Inactivating mu-tations in this pathway result in dysregulated cell growthand protein synthesis, providing potential insight into themolecular mechanisms involved in BHDS [6,7,15,16,21,22].

Although unclear whether insufficient FLCN stimulatesor suppresses the mTOR pathway, some studies havedemonstrated increases in downstream molecules, such asS6 kinase and hypoxia-inducible factor 1-alpha (HIF-1a), inhuman BHDS renal tumors. In the lung, cyst-lining cells haveshown immunostaining positivity for phospho-mTOR andphospho-S6 ribosomal protein, suggesting that they areunder activated conditions [2,13,15,23]. As neoplasticproliferation is absent in cyst-lining cells, the mTORpathway may be less distinctively deviated in pulmonarycysts than in renal cell cancers [15].

The mechanisms of cyst development under the condi-tion of FLCN haploinsufficiency remain poorly understood.If accelerated mTOR signaling directly induces cysticremodeling, downstream molecules such as S6 ribosomalprotein may play a key role in pathogenesis. HIF-1a is a keymolecule contributing to aberrant angiogenesis in manytypes of cancer. Proliferation of blood vessels was noted inthe vicinity of pulmonary cysts [15]. Accelerated angiogenicsignaling is due in part to increases in HIF-1a and vascularendothelial growth factor associated with FLCN hap-loinsufficiency. These histopathologic findings support thenotion that the activation of angiogenic signaling contrib-utes to the development of BHDS-associated pulmonarycysts [15].

The involvement of mTOR pathway in the pathogenesis ofBHDS is also suggested by the phenotypic similarities of thissyndrome to tuberous sclerosis complex (TSC), which isknown to be caused by mTOR pathway dysregulation. How-ever, this is not the only signaling pathway implicated in thetumor suppressing action of the FLCN gene [2,15,18,24].

In the past several years, lung cyst pathogenesis hasbeen widely studied in pulmonary cystic diseases, such as

Please cite this article in press as: Dal Sasso AA, et al., Birt-Hogg-Dubinvolvement, Respiratory Medicine (2014), http://dx.doi.org/10.1016/

lymphangioleiomyomatosis (LAM), Langerhans cell histio-cytosis (LCH), and cystic lung light chain deposition disease[25]. Metalloproteinases appear to have an important rolein cyst formation [9,25]. These proteins belong to a familyof proteolytic enzymes mostly responsible for maintainingextracellular matrix remodeling, but they also affect cellmigration, angiogenesis, and pulmonary immunity. FLCNmutations may alter cytokines and proteases, which areimportant for extracellular matrix integrity. The pulmonaryarchitecture depends on interactions between collagen andelastin fibers in the extracellular matrix, which maintainalveolar wall integrity. The overexpression of metal-loproteinases leads to matrix breakdown, tissue destruc-tion, and cystic lesions [9,25].

Pathology

Although the pathology of renal and cutaneous manifesta-tions of BHDS has been well described, few reports havedescribed the histological characteristics of associatedpulmonary cysts [2]. In contrast to the neoplastic process inthe skin and kidney, no neoplastic changes have been re-ported in association with lung involvement [21,26].

By definition, cysts are well-circumscribed usually roundspaces with epithelial or fibrous walls of variable thickness.Macroscopically, cysts in BHDS are often elongated andsubpleural in distribution, with the total extent of lunginvolvement being less than 30% [27,28].

Microscopically, they are lined with pneumocytes andpartially enveloped by septal and/or pleural interstitialtissue. Alveolar cells lining the inner surface of the cystshow positive immune-staining for epithelial markers andsurfactant proteins. They may be attenuated or not easilyvisible; however, cuboidal cells resembling type II pneu-mocytes are often observed in the innermost layer [9,17].No reactive stromal proliferation or inflammation are pre-sent, except in case of rupture. The cyst wall extends to-ward the visceral pleura and is partially incorporated intothe parenchyma, interlobular septum, and/or bronchovas-cular bundle. In some cases, the walls are partially envel-oped by other alveolar walls, demonstrating an uniquearrangement of an alveolus or a few alveoli within the cyst.Occasionally, small veins protrude into the cystic space.These characteristic findings are important microscopicclues for the pathological diagnosis of BHDS [21,23].

Pulmonary cysts in BHDS are distinct from bullae,defined as cystic air spaces generated by destruction ofalveolar walls, and blebs, defined as intrapleural localizedair-containing lesions. However, examination of rupturedcysts can be misleading [2]. The histopathology of rupturedcysts causing pneumothorax is complicated due to me-chanical stress and tissue remodeling with associatedinflammation. Pleural thickening, interstitial bleeding, andhyalinization alter the original cyst architecture. Afterrupture, mesothelial invagination and bleb formation arefrequently observed. Cystic alveoli and fusion of the cystepithelium to the mesenchyme are diagnostic clues toBHDS-associated lung lesions, even at advanced stages withinflammatory changes [2,17,21,29]. The interlobular septain contact with a cyst may be edematous, possibly theresult of localized disturbance of circulation and venous


Figure 2 A 54-year-old woman with Birt-Hogg-Dube syn-drome. Axial computed tomography with the lung window atthe level of the lower lobes shows right pneumothorax. Inaddition, small round and ovoid cysts are visible in the pul-monary parenchyma.


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stasis. Other possible causes of edema include FLCN insuf-ficiency, which may lead to matrix remodeling, and angio-genic factors leading to increased vascular permeability[17].

Pulmonary manifestations

Pulmonary cysts (Fig. 1) and repeated episodes of pneu-mothorax (Fig. 2) are clinical hallmarks of BHDS. Lunginvolvement is often the earliest phenotypical manifesta-tion to appear, and pneumothorax may be the only mani-festation of the syndrome in some patients [5,17,30].However, most affected patients are asymptomatic. Olderpatients and those with more severe lung involvement aremore likely to have symptoms, particularly dyspnea andcough [1,18,25].

Cystic lung lesions likely develop in early to mid-adulthood (30e40 years), but have been described in pa-tients ranging in age from 20 to 85 years [2]. A 50-fold in-crease in riskof pneumothorax has been described inpatients with BHDS [7], and correlates inversely with age

Figure 1 A 38-year-old woman with Birt-Hogg-Dube syn-drome. High-resolution computed tomography at the level ofthe lower lobes (A) and coronal reconstruction (B) show thin-walled, round and ovoid pulmonary cysts predominating inthe lower-medial zones of both lungs.


[5,31]. Cyst size and volume correlate with increased risk ofpneumothorax [6]. Although smoking is an important riskfactor for primary spontaneous pneumothorax, no associa-tion between smoking history and the presence or fre-quency of pneumothorax has been found in patients withBHDS [7,18,32]. The severity of cutaneous involvement andthe presence of kidney tumors do not correlate with theoccurrence of pneumothorax [6].

Various other thoracic abnormalities, including pulmo-nary malignancy, and congenital chest malformation, havebeen observed in patients with BHDS. However, it remainsunclear whether any of these abnormalities is causallyrelated to the disease [2,17,18,33,34].

Cutaneous manifestations

Skin manifestations of BHDS usually appear in the third andfourth decades of life [35,36]. Birt and colleagues [3]described fibrofolliculomas (Fig. 3), trichodiscomas, andacrochordons as the triad of skin lesions characterizingBHDS. Currently, fibrofolliculomas and trichodiscomas areconsidered to be part of a morphological spectrum. In pa-tients with BHDS, acrochordons may represent a phenotypicvariant of fibrofolliculoma; however, they occur in thegeneral population and cannot be used alone for the diag-nosis of the syndrome [3,17e19,37].

Clinically, these lesions present as multiple, asymp-tomatic, firm, whitish papules with 2e4-mm diameters anda dome-shaped appearance, located mainly in the nose,forehead, and cheeks [5,8,10,12]. Other skin lesions lessfrequently seen in BHDS include lipomas, angiolipomas,mucous fibromas, melanoma, and collagenoma [16,19]. Thepresence of facial angiofibromas has occasionally been re-ported, although these lesions are more typically associ-ated with TSC [6,18,35,38]. Specific dermatologicalmanifestations may be helpful in distinguishing inheritableskin disorders which also include TSC, LCH, Marfan’s syn-drome and Ehlers-Danlos syndrome [6].


Figure 3 A 66-year-old man with Birt-Hogg-Dube syndrome.Multiple firm, white to skin-colored papules are visible on thenose and in the paranasal area. Biopsy demonstrated thatthese were fibrofolliculomas.

Figure 4 66-year-old man with Birt-Hogg-Dube syndrome.Axial in-phase T1-weighted magnetic resonance image (A)shows that the mass (arrows) has high signal intensity on T1,consistent with hemorrhagic or high proteinaceous content.Coronal HASTE T2-weighted magnetic resonance image (B)shows a large heterogeneous exophytic mass in the upper halfof the left kidney (arrows). There are central areas of necroticdegeneration with high T2 signal intensity. Cysts are seen onthe liver and on right kidney (arrowheads). Note also thehypointense rim on T1 and T2-weighted images around thetumor.


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Renal manifestations

The most serious complication of BHDS is renal cancer(Fig. 4). The prevalence of renal tumors in these patients is23e34%, with a sevenfold increased risk of malignancywhen compared to the general population. Histologicalsubtypes include chromophobe oncocytomas (50%), chro-mophobe carcinomas (34%), clear cell carcinomas (9%),oncocytomas (5%), and papillary renal cell cancers (2%)[1,5,7,8,14,26]. Most renal tumors are bilateral, multifocal,and slow growing [11,13,19,24]. Benign renal cysts havealso been documented in patients with BHDS, but the exactprevalence in comparison to the general population iscurrently unknown [18,19,24]. Renal angiomyolipoma oc-casionally occurs in association with BHDS, but it is morefrequent in patients with TSC [1,5,15,24].

Other clinical findings

Several other lesions have been reported in BHDS includingbenign entities such as multinodular goiter, parathyroidadenoma, parotid-gland adenoma and oncocytoma, colo-rectal polyp and adenoma, neural tissue tumor, tricho-blastoma, connective tissue nevus, focal cutaneousmucinosis and cutaneous leiomyoma [5,10,11,18]. Malig-nant tumors include breast cancer, colorectal cancer, sar-coma of the leg, tonsillar cancer, basal and squamous-cellskin cancer, dermatofibrosarcoma protuberans, and cuta-neous leiomyosarcoma [5,7,10,11,18]. Other abnormalitiesobserved in patients with BHDS include flecked chorior-etinopathy, bullous emphysema, and internal carotid arteryaplasia [11,18]. However, their causal association withBHDS has not been clinically validated [16,18].

Pulmonary imaging findings

On computed tomography (CT), pulmonary cysts generallymanifest as a rounded lesion with well-defined interface


with normal lung parenchyma, usually containing air, or lesscommonly fluid. Cysts have variable wall thickness, usually<2 mm [28,39].

Certain CT imaging characteristics may suggest thediagnosis of BHDS-related cystic lung disease. In these pa-tients, cyst location differs from the typical apical locationof smoking-related emphysema and bullae/blebs seen inprimary spontaneous pneumothorax [2]. In BHDS, cysts aretypically located in the lower lung regions, distributedbilaterally, and intimately related to interlobular septaand/or visceral pleura, pulmonary arteries, and veins[8,18,29]. The number of cysts is quite variable [2,6,40] andtheir size range from a few millimeters to >2 cm althoughsmall (<1 cm) cysts are most commonly seen. The


Table 1 Proposed diagnostic criteria for BHD [2].

Definite pulmonary BHD

1. Characteristica or compatibleb lung HRCT and skin biopsypositive for fibrofolliculoma or trichodiscoma

2. Characteristic or compatible lung HRCT and confirmedfamily history of BHD in first or second degree familymember

3. Characteristic or compatible HRCT and tissueconfirmation of renal chromophobe adenoma oroncocytoma

4. Characteristic or compatible HRCT and tissueconfirmation of genetic testing positive for BHD

Probable pulmonary BHD

1. Characteristic HRCT, exclusion of TSC and LAM, andpersonal or family history of pneumothorax

2. Compatible HRCT, exclusion of TSC and LAM, and any ofthe following:a. Family or personal history of renal tumorsb. Skin angiofibromac. Renal angiomyolipoma

Possible pulmonary BHD

Compatible or characteristic HRCT.a Characteristic lung HRCT findings: Multiple thin-walled

round, elliptical or lentiform well-defined air-filled cysts,without internal structure, in a basilar, medial and subpleuralpredominant distribution, with preserved or increased lungvolume, and no other significant pulmonary involvement (spe-cifically no interstitial lung disease).b Compatible HRCT findings: Thin walled cysts without the

more typical elliptical shape or subpleural distribution.


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morphology of lung cysts varies within and amongst pa-tients, ranging from round to oval, lentiform, and lobu-lated/multiseptated. Cyst walls tend to be perceptible,thin, and uniform [8]. Tobino et al. [40] reported that mostpulmonary cysts in patients with BHDS were irregularlyshaped and that their extent did not change over time. Cystsize, morphology, and distribution patterns seem to beinherited within affected families and differ amongdifferent family groups [41,42].

Pulmonary function tests

Despite the presence of multiple lung cysts, pulmonaryfunction tests are usually normal or only mildly abnormal inpatients with BHDS [5,6,18]. Nevertheless, diffusion ca-pacity for carbon monoxide (adjusted for alveolar volume)was found to be mildly decreased, and absolute forcedexpiratory volume in 1 s was inversely correlated with cystarea measured by CT [2].

Diagnosis

The diagnosis of BHDS should be suspected in young patientspresenting with spontaneous pneumothorax, especiallythose with personal or family history of pneumothorax, skinlesions, or renal tumors [2,5,20]. In the system proposed byMenko et al. [18], the diagnosis of BHDS should be based onfulfillment of one major criterion (at least five adult-onsetfibrofolliculomas with histological confirmation of at leastone; pathogenic FLCN germline mutation) or two minorcriteria[multiple bilateral, basally located lung cysts with noother apparent cause, with or without spontaneous primarypneumothorax; early-onset (<50 years of age), multifocal,or bilateral renal cancer, or renal cancer of mixed chro-mophobe and oncocytic histology; first-degree relative withBHDS]. However, BHDS should be considered even in pa-tients who do not fulfill the diagnostic criteria but have anunderlying FLCN mutation [2,17,18,28].

New diagnostic criteria based mainly on chest CT char-acteristics of pulmonary cysts have been recently proposed[2] (Table 1).

Imaging criteria for differential diagnosis

The main differential diagnosis of BHDS include cystic lungdiseases, particularly LAM, lymphocytic interstitial pneu-monia (LIP), LCH and Pneumocystis jiroveci pneumonia[1,2,8]. The distribution of cysts along with ancillary find-ings on imaging studies may be helpful in distinguishingthese entities [6,27]. Diseases such as Marfan syndrome,homocystinuria, Ehler-Danlos syndrome, and alpha-oneantitrypsin deficiency can present with familial historiesof spontaneous pneumothorax and should also be consid-ered in the differential diagnosis of BHDS [2,6,8,21].

The presence of cysts in the setting of an autoimmunedisease, particularly Sjogren syndrome, is very suggestiveof LIP, which presents on CT as ground-glass opacities,poorly defined centrilobular nodules, and thin-walled cystswith a basal predominance. Although cysts may vary in size,they are often <30 mm in diameter and sparse. Additional


CT findings reported in LIP include peribronchovascularthickening, interlobular septal thickening, subpleural nod-ules, lymphadenopathy, and areas of consolidation [27,43].Pulmonary LCH is a smoking-related lung disease that in-cludes bronchiolocentric stellate interstitial nodules. Thenodules may subsequently cavitate and form thick- andthin-walled cysts. Frequently, nodules and cysts are seensimultaneously. The cysts are often irregular, bilobed orbizarrely shaped. P. jiroveci pneumonia is seen in patientswith immunosupression with acute or subacute respiratorysymptoms and typically presents on imaging studies withbilateral ground-glass opacities, occasionally with consoli-dation and nodules. Cystic lesions, or pneumatoceles, occurin approximately 30% of the cases, are typically transientand have upper zone predominance. Spontaneous pneu-mothorax can also occur [8,27].

Amongst the cystic lung diseases, LAM is the most difficultto differentiate from BHDS, especially when associated withTSC with renal and cutaneous involvement [1,2]. Similar toBHDS, TSC has a wide clinical spectrum. Patients with TSCusually show angiomyolipomas (70e90%), angiofibromas,hypopigmented macules, shagreen patch, and/or periungualfibromas [6]. Pulmonary LAM is a rare progressive diseasethat predominantly affects women of childbearing age. Menmay be affected in the setting of underlying TSC. Globally,LAM associated with TSC is 5- to 10-fold more common thansporadic LAM. Clinical manifestations include shortness ofbreath, cough, chest pain, chylous pleural effusions, he-moptysis, and occasionally respiratory failure although



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asymptomatic cases may occur. Spontaneous or recurrentpneumothorax may be the presenting finding in up to 50% ofpatients with LAM [44]. It has been suggested that LAMassociated with TSC most closely mimics BHDS on radiolog-ical exams. Cysts in BHDS and LAM are thin walled, but thoseassociated with LAM are smaller and more circular, homo-geneous, and equally distributed. The intervening lung pa-renchyma is typically normal in LAM although smallcentrilobular nodules, septal thickening, and focal ground-glass opacities have been reported [2,8,24,27].

Treatment

Patients with BHDS require evaluation by a multidisciplinaryteam and through investigation for multisystem complica-tions. From a pulmonary perspective, treatment is largelyfocused on treatment and prevention of pneumothorax.The management of pneumothorax in patients with BHDSdiffers from that recommended for patients with primaryspontaneous pneumothorax and is similar to that proposedfor patients with LAM. Given the high recurrence rate,surgical intervention with resection and pleurodesis is anacceptable option, even in patients with a first episode ofpneumothorax [2,5,41]. The prognosis of BHDS and LAM isquite different. LAM usually progresses to respiratoryinsufficiency, and BHDS does not [42]. LAM is extremelydifficult to treat, and the long-term prognosis is poor [44].On the other hand, BHDS lung cysts or pneumothoraceswere not associated with fatalities or chronic debilitation[6]. Patients should be informed that BHD cystic lung dis-ease typically does not result in respiratory failure. How-ever, patients with lung function impairment should beregularly followed by pulmonologists and periodic mea-surement of pulmonary function should be performed [2].

Patients should be cautioned about the increased risk ofpneumothorax in association with scuba diving and airtravel. Although no specific recommendations are availablefor BHDS, the British Thoracic Society guidelines [45]consider the presence of lung cysts and bullae a contrain-dication to diving due to increased risk of barotrauma andpneumothorax. In general, air travel is considered safe formost patients with BHDS [5,45]. Regular immunization andperiodic measurement of pulmonary function should beperformed in patients with BHDS. In addition, pneumo-coccal and annual influenza vaccination should be stronglyencouraged [2].

The main concern in BHDS is the development of renalcarcinoma [11,12]. Annual physical examination, magneticresonance imaging, and/or ultrasonography have been re-ported to be the best surveillance tools [30]. Due to theirbenign nature, no specific medical treatment is warrantedfor the cutaneous lesions of BHDS [11]. If required, surgicalremoval is the treatment of choice for solitary perifollicularfibromas whereas electrodessication may be helpful inremoving multiple lesions [13].

Conclusion

BHDS is a rare yet important genetic condition that remainsunderdiagnosed partly due to variable clinical presenta-tion. The presence of multiple papular skin lesions, renal


lesions, and/or a family history of pneumothorax or renalmalignancy are important diagnostic clues. Pulmonary cystson imaging studies may be the initial manifestation and areoften the finding to first suggest the diagnosis, highlightingthe role of CT in early diagnosis.

Awareness of the clinical manifestation of BHDS by pul-monologists and radiologists is pivotal in patients care as itallows early detection and management of complications,particularly renal malignancy.

Conflict of interest statement

The authors have no conflict of interest.

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