Baldi, Bruno Guedes

Carvalho, Carlos Roberto Ribeiro

Kairalla, Ronaldo Adib

Mauad, Thais

Nascimento, Ellen Caroline Toledo do

Pimenta, Suzana Pinheiro

English

Cadernos Espinosanos (E-Journal)

CASE REPORTBirt-Hogg-Dube´ syndrome: metalloproteinaseactivity and response to doxycyclineSuzana Pinheiro Pimenta,I Bruno Guedes Baldi,I Ellen Caroline Toledo do Nascimento,II Thais Mauad,IIRonaldo Adib Kairalla,I Carlos Roberto Ribeiro CarvalhoII Faculdade de Medicina da Universidade de Sa˜o Paulo, Heart Institute (InCor), Pulmonary Division, Sa˜o Paulo/SP, Brazil. II Faculdade de Medicina daUniversidade de Sa˜o Paulo, Department of Pathology, Sa˜o Paulo/SP, Brazil.Email: spp3847@yahoo.com.brTel.: 55 11 8232-6007INTRODUCTIONBirt-Hogg-Dube´ syndrome (BHDS) is a rare, inheritedautosomal-dominant genodermatosis caused by mutationsin the folliculin gene (FLCN), which is located within thechromosomal band 17p11.2 (1). Patients with BHDS areprone to fibrofolliculomas, trichodiscomas, and acrochor-dons on the face, neck, and upper trunk; renal tumors;pulmonary cysts; and spontaneous pneumothorax (2-4).The pathogenesis of lung cyst formation and pneu-mothorax remains unclear, but studies have shown thatfolliculin is strongly expressed in lung fibroblasts andmacrophages. Folliculin mutations may alter cytokines andproteases, which are important in maintaining extracellularmatrix (ECM) integrity, leading to an inflammatory re-sponse and matrix degradation with subsequent remodeling(5,6).The pulmonary architecture depends on interactionsbetween collagen and elastin fibers in the ECM, whichmaintain alveoli wall integrity (7). The overexpression ofmetalloproteinases (MMPs), regardless of whether they areassociated with the suppression of tissue inhibitors ofmetalloproteinases (TIMPs), leads to matrix breakdown,tissue destruction and cystic lesions (7,8).Because there is currently no treatment for BHDS, wedecided to describe our experience treating one BHDSpatient with doxycycline, which is an MMP inhibitor (9) thathas been previously used to treat cystic lung disease (10).Case DescriptionA 44-year-old female non-smoker complained of milddyspnea upon exertion in 2004 and presented with a spon-taneous pneumothorax in 2005. Chest computed tomogra-phy (CT) demonstrated bilateral thin-walled cystic lesions(Figure 1). Pulmonary functional tests (PFTs) showed normalcarbon monoxide diffusion capacity (DLCO=81% of thepredicted value), lung volume, and expiratory flow rate,but an increased residual volume (RV) and total lungcapacity (TLC) ratio (RV/TLC=0.45) were found, as shownin Table 1. An abdominal CT was also normal. A lung biopsyand pleurodesis by videothoracoscopy were performed, andthe patient was diagnosed with lymphangioleiomyomatosis(LAM). She was referred to our institution in 2006 toparticipate in a doxycycline treatment protocol.All patients with a diagnosis of LAM who were enrolledin this protocol were submitted to lung function evaluationand ELISA-based quantitative serum and urinary MMP-2and -9 analysis (R&D Systems; Minneapolis, MN, USA)before and after doxycycline treatment (11).After six months of receiving doxycycline (100 mg/day),the patient noticed resolution of the exertional dyspnea andimprovement in exercise tolerance. After treatment, DLCOand forced vital capacity (FVC) showed increases from 16.8to 19.7 mL/min/mmHg and 2.87 to 3.12 L, respectively.The forced expiratory volume in the first second (FEV1), RVand RV/TLC values pre- and post-doxycycline were,respectively, 2.36 and 2.35 L, 2.23 and 1.51 L, and 0.45 and0.32 (Table 1).The MMP blockade induced by doxycycline was effective,resulting in a reduction in serum MMP-9 levels from 143 to36 ng/mL, and urinary levels of MMP-9 became untrace-able (55 pg/mL before doxycycline). MMP-2 levels were notdetectable before or after treatment.During follow-up, the patient presented with soft andpedunculated papules on her neck and upper thorax. Thebiopsy of these lesions was compatible with acrochordons.The patient’s family medical history also revealed othercases of cystic lung disease (Figure 2).The lung biopsy specimen was reviewed in 2007.Histological analysis of the lung tissue revealed severalcystic areas with an emphysematous aspect in the lungparenchyma, mostly in the subpleural region. Cyst wallswere formed by collapsed alveolar parenchyma or slightlythickened pleural tissue. LAM cells were not observed in thecyst walls, and monoclonal antibody HMB-45 (humanmelanoma black-45), S100 protein and alpha smooth muscleactin were also not observed (Figure 3).Based on the family history, the presence of cutaneouslesions (acrochordons), the CT findings and the lunghistological review, the diagnosis of BHDS was established.The positive response to doxycycline treatment, whichhad never been demonstrated in BHDS, and the associationbetween the loss-of-function mutation in folliculin andpulmonary extracellular matrix degradation (6), led us toevaluate MMP behavior in lung tissue.Immunohistochemical analysis in the patient’s lung tissuerevealed a large number of MMP-9-positive cells, mostlyCopyright  2012 CLINICS – This is an Open Access article distributed underthe terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.No potential conflict of interest was reported.CLINICS 2012;67(12):1501-1504 DOI:10.6061/clinics/2012(12)251501macrophages and neutrophils, in the cyst wall, whereas theadjacent lung parenchyma presented scattered MMP-9-positive cells along the alveolar walls (figure 3). MMP-2staining showed scattered positive inflammatory cells in thelung parenchyma with no specific cyst staining.During the subsequent months, the patient developedgastric intolerance symptoms, leading to the interruption ofdoxycycline therapy. Spirometry performed 18 months afterdoxycycline interruption revealed a decrease in lungvolume and expiratory flow rates (Table 1) with worseningof the pulmonary symptoms.DISCUSSIONIn a non-smoking female who develops spontaneouspneumothorax and presents with cysts in the thoracic highresolution CT, LAM is a strong diagnostic possibility.However, other cystic lung disorders, such as BHDS, mayhave the same presentation.In the past several years, lung cyst pathogenesis has beenwidely studied in pulmonary cystic diseases, such as LAM,Langerhans cell histiocytosis (LCH) and cystic lung lightchain deposition disease (CL-LCDD). MMPs appear to havean important role in the pathogenesis of cyst formation(8,12-14). These proteins belong to a family of proteolyticenzymes and are classified according to their specificsubstrates into gelatinases (MMP-2 and -9), interstitialcollagenases (MMP-1, -8 and -13) and stromelysins (MMP-3, -7 and -10). These enzymes are mainly responsible forECM remodeling, but they also affect cell migration,angiogenesis and pulmonary immunity (7,15,16).In LAM, lung cyst development is affected by MMP-2and -9 upregulation in LAM cells (abnormal smoothmuscle-like cells) rather than in vascular and bronchiolarsmooth muscle cell (14,17). High serum MMP-9 levels arealso present in the blood of patients with LAM (17). Zheet al. described the downregulation of TIMPs, especiallyTIMP-3, followed by MMP-2 and -14 overexpression, inLAM cells (18).LCH is characterized by irregularly dilated alveolarspaces and degraded elastic fibers that are surrounded bygranulomatous lesions. An immunohistochemical studyshowed MMP-2 expression in the epithelial basementmembranes of these damaged areas and collagen type IVimpairment (12,19).Figure 1 - High-resolution chest CT. A) A CT scan showing thin-walled, air-filled cystic lesions, including one dominant cyst (665 cm).B) In addition to the cystic lesions, posterior pleural thickening due to previous pleurodesis is observed on the right side.Table 1 - Pulmonary function tests performed before and during doxycycline treatment and 18 months after doxycyclineinterruption.Before doxy During doxy After doxyPulmonary function variables 3 months 6 months 18 monthsFVC - L (% pred) 2.87 (82) 3.03 (83) 3.12 (85) 2.33 (70)FEV1 - L (% pred) 2.36 (87) 2.34 (79) 2.35 (80) 2.21 (80)FEV1/ FVC 0.82 0.77 0.76 0.95TLC - L (% pred) 4.87 (94) x 4.74 (93) xRV/TLC (% pred) 0.45 (137) x 0.32 (97) xDLco - mL/min/mmHg (% pred) 16.84 (81) x 19.7 (80) xFVC: forced vital capacity; FEV1: forced expiratory volume in the first second; TLC: total lung capacity; RV: residual volume; DLCO: carbon monoxidediffusion capacity.Figure 2 - Pedigree of the family. Square =male member,circle = female member; solid symbol = pneumothorax, opensymbol =no pneumothorax; slash through symbol= cystic lesionson lung CT; * our patient.Doxycycline in Birt-Hogg-Dube´ syndromePimenta SP et al.CLINICS 2012;67(12):1501-15041502Pulmonary involvement is especially rare in light chaindeposition disease (LCDD), which is a systemic disordercharacterized by diffuse monoclonal nonamyloid light chaindeposits. There are two types of lung impairment: nodularand CL-LCDD. In CL-LCDD, giant macrophagic cellslocated around light chain deposits express MMP-2, -9,and -14, which can degrade the elastic network (8,20).BHDS, an inherited and rare disorder caused by an FLCNmutation, presents with dermatologic and pulmonaryinvolvement and usually manifests during the third orfourth decade of life (2,3). Patients with BHDS have anincreased risk of renal cell carcinoma, colorectal neoplasia(3,21) and parotid oncocytomas (22). Abnormal pleuropul-monary findings include lung cysts, pleural blebs andspontaneous pneumothorax (4). Histopathological studiesare very limited, especially studies investigating cystic lungpathogenesis. Butnor and Guinee (23) described nonspecificfeatures in the lung biopsies of two BHDS patients, showingintraparenchymal air-filled spaces surrounded by normalparenchyma or a thin fibrous wall. Lung tissue adjacent tothe cysts appeared normal. In our patient, we observedsubpleural cysts within the lung parenchyma, formed bycollapsed alveolar walls with a connective tissue lining.In contrast to the descriptions of other cystic lungdiseases, where a histopathological substrate was presentduring pulmonary cystic growth, we found lesions resem-bling emphysema surrounded by normal lung tissue in thisBHDS case.MMP behavior has not been previously described inBHDS. In our pulmonary immunohistochemical analysis,MMP-9 was expressed in a large number of cells, mostlymacrophages and neutrophils, located in the cyst wall.However, the lung parenchyma adjacent to the cyst wallpresented only a few scattered MMP-9-positive cells. Thesefindings suggest that MMP-9, as in other lung cysticdisorders, may be implicated in BHDS cyst development.Based on the improvement in pulmonary function and thedecrease in urinary and serum MMP-9 levels observed inour patient, doxycycline, a known inhibitor of tissue MMPs,may represent a promising therapy for BHDS.ACKNOWLEDGMENTSWe would like to thank Shari Anne El-Dash for the language revision.AUTHOR CONTRIBUTIONSPimenta SP diagnosed the patient, wrote the case presentation andcontributed to the literature review. Baldi BG contributed to the literaturereview. Kairalla RA diagnosed the patient and contributed to thepresentation of the case. Nascimento ECT and Mauad T contributed tothe histopathological diagnosis. Carvalho CRR coordinated the manu-script and was responsible for the final review. All authors read andapproved the final manuscript.REFERENCES1. Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ,et al. Germline BHD-mutation spectrum and phenotype analysis of alarge cohort of families with Birt-Hogg-Dube syndrome. Am J HumGenet. 2005;76(6):1023-33, http://dx.doi.org/10.1086/430842.2. Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas withtrichodiscomas and acrochordons. Arch Dermatol. 1977;113(12):1674-7,http://dx.doi.org/10.1001/archderm.1977.01640120042005.3. Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, et al. Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia. ArchFigure 3 - Histopathological analysis of cystic lung lesions. A) A large subpleural cyst within the lung parenchyma. The cyst formed bythe collapse of the alveolar walls with a connective tissue lining (H&E staining; 40x magnification). B) Details of a smaller cyst stainedwith an anti-alpha smooth muscle actin antibody. There are no positive LAM cells in the cyst wall. Adjacent blood vessel walls expressactin. V= vessel, C= cyst (400x magnification). C) Details of a subpleural cyst wall with a large number of MMP-9-positive cells, mostlymacrophages and neutrophils, in the cyst wall (400x magnification). D) Normal lung parenchyma adjacent to the cyst wall, showingscattered MMP-9-positive cells (arrow) in the alveolar walls (400x magnification).CLINICS 2012;67(12):1501-1504 Doxycycline in Birt-Hogg-Dube´ syndromePimenta SP et al.1503Dermatol. 1999;135(10):1195-202, http://dx.doi.org/10.1001/archderm.135.10.1195.4. Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, et al.Lung cysts, spontaneous pneumothorax, and genetic associations in 89families with Birt-Hogg-Dube syndrome. Am J Respir Crit Care Med.2007;175(10):1044-53, http://dx.doi.org/10.1164/rccm.200610-1483OC.5. Frohlich BA, Zeitz C, Matyas G, Alkadhi H, Tuor C, Berger W, et al.Novel mutations in the folliculin gene associated with spontaneouspneumothorax. Eur Respir J. 2008;32(5):1316-20, http://dx.doi.org/10.1183/09031936.00132707.6. Kalhan R, Yeldandi AV, Jain M. A 48-year-old woman with skin lesions,renal masses, and spontaneous pneumothorax. Chest. 2007;131(2):624-7,http://dx.doi.org/10.1378/chest.06-0559.7. Elkington PT, Friedland JS. Matrix metalloproteinases in destructivepulmonary pathology. Thorax. 2006;61(3):259-66, http://dx.doi.org/10.1136/thx.2005.051979.8. Colombat M, Caudroy S, Lagonotte E, Mal H, Danel C, Stern M, et al.Pathomechanisms of cyst formation in pulmonary light chain depositiondisease. Eur Respir J. 2008;32(5):1399-403, http://dx.doi.org/10.1183/09031936.00132007.9. Chung AW, Yang HH, Radomski MW, van Breemen C. Long-termdoxycycline is more effective than atenolol to prevent thoracic aorticaneurysm in marfan syndrome through the inhibition of matrixmetalloproteinase-2 and -9. Circ Res. 2008;102(8):e73-85, http://dx.doi.org/10.1161/CIRCRESAHA.108.174367.10. Moses MA, Harper J, Folkman J. Doxycycline treatment for lymphan-gioleiomyomatosis with urinary monitoring for MMPs. N Engl J Med.2006;354(24):2621-2, http://dx.doi.org/10.1056/NEJMc053410.11. Pimenta SP, Baldi BG, Acencio MM, Kairalla RA, Carvalho CR.Doxycycline use in patients with lymphangioleiomyomatosis: safetyand efficacy in metalloproteinase blockade. J Bras Pneumol.2011;37(4):424-30, http://dx.doi.org/10.1590/S1806-37132011000400003.12. Hayashi T, Rush WL, Travis WD, Liotta LA, Stetler-Stevenson WG,Ferrans VJ. Immunohistochemical study of matrix metalloproteinasesand their tissue inhibitors in pulmonary Langerhans’ cell granuloma-tosis. Arch Pathol Lab Med. 1997;121(9):930-7.13. Hayashi T, FlemingMV, Stetler-StevensonWG, Liotta LA, Moss J, FerransVJ, et al. Immunohistochemical study of matrix metalloproteinases(MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangio-leiomyomatosis (LAM). Hum Pathol. 1997;28(9):1071-8, http://dx.doi.org/10.1016/S0046-8177(97)90061-7.14. Matsui K, Takeda K, Yu ZX, Travis WD, Moss J, Ferrans VJ. Role foractivation of matrix metalloproteinases in the pathogenesis of pulmonarylymphangioleiomyomatosis. Arch Pathol Lab Med. 2000;124(2):267-75.15. Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, et al. Amatrix metalloproteinase expressed on the surface of invasive tumourcells. Nature. 1994;370(6484):61-5, http://dx.doi.org/10.1038/370061a0.16. Jackson C. Matrix metalloproteinases and angiogenesis. Curr OpinNephrol Hypertens. 2002;11(3):295-9, http://dx.doi.org/10.1097/00041552-200205000-00005.17. Odajima N, Betsuyaku T, Nasuhara Y, Inoue H, Seyama K, NishimuraM. Matrix metalloproteinases in blood from patients with LAM. RespirMed. 2009;103(1):124-9, http://dx.doi.org/10.1016/j.rmed.2008.07.017.18. Zhe X, Yang Y, Jakkaraju S, Schuger L. Tissue inhibitor of metallopro-teinase-3 downregulation in lymphangioleiomyomatosis: potential con-sequence of abnormal serum response factor expression. Am J RespirCell Mol Biol. 2003;28(4):504-11, http://dx.doi.org/10.1165/rcmb.2002-0124OC.19. Fukuda Y, Basset F, Soler P, Ferrans VJ, Masugi Y, Crystal RG.Intraluminal fibrosis and elastic fiber degradation lead to lung remodel-ing in pulmonary Langerhans cell granulomatosis (histiocytosis X).Am J Pathol. 1990;137(2):415-24.20. Bhargava P, Rushin JM, Rusnock EJ, Hefter LG, Franks TJ, Sabnis SG,et al. Pulmonary light chain deposition disease: report of five cases andreview of the literature. Am J Surg Pathol. 2007;31(2):267-76.21. Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, et al.Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet.2002;39(12):906-12, http://dx.doi.org/10.1136/jmg.39.12.906.22. Maffe A, Toschi B, Circo G, Giachino D, Giglio S, Rizzo A, et al.Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dube syndrome ascertained for non-cutaneous manifestations. ClinGenet. 2011;79(4):345-54, http://dx.doi.org/10.1111/j.1399-0004.2010.01480.x.23. Butnor KJ, Guinee DG, Jr. Pleuropulmonary pathology of Birt-Hogg-Dube syndrome. Am J Surg Pathol. 2006;30(3):395-9.Doxycycline in Birt-Hogg-Dube´ syndromePimenta SP et al.CLINICS 2012;67(12):1501-15041504

Birt-Hogg-Dubé syndrome: metalloproteinase activity and response to doxycycline

https://www.revistas.usp.br/clinics/article/download/52300/56327

Birt-Hogg-Dubé syndrome: metalloproteinase activity and response to doxycycline

Abstract

Similar works

Full text

Available Versions

Cadernos Espinosanos (E-Journal)