ANTICANCER RESEARCH 30: 751-758 (2010)

Review Association Between Birt Hogg Dubé Syndrome and Cancer Predisposition

RAFFAELE PALMIROTTA1, ANNALISA SAVONAROLA1, GIORGIA LUDOVICI1, PIETRO DONATI2, FRANCESCO CAVALIERE3, MARIA LAURA DE MARCHIS1, PATRIZIA FERRONI1 and FIORELLA GUADAGNI1

1Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, 00165 Rome, Italy; 2Unit of Histopathology, IRCCS San Gallicano Dermatologic Institute, 00144 Rome, Italy; 3Breast Unit, San Giovanni Hospital, 00184 Rome, Italy

Abstract. The Birt Hogg Dubé syndrome (BHD) is a rare Clinically, the BHD syndrome exhibits numerous autosomal dominant genodermatosis predisposing patients to asymptomatic, skin colored, dome-shaped papules over the developing fibrofolliculoma, trichodiscoma and acrochordon. face, neck, and upper trunk. These lesions represent benign The syndrome is caused by germline in the folliculin proliferations of the ectodermal and mesodermal components (FLCN) , encoding the folliculin tumor-suppressor of the pilar apparatus (2). Fibrofolliculomas are benign . Numerous mutations have been described in the tumors of the perifollicular connective tissue, occurring as FLCN gene, the most frequent occurring within a C8 tract of one or more yellowish dome-shaped papules, usually on the 11. This hypermutability is probably due to a slippage in face. Trichodiscomas are parafollicular mesenchymal DNA polymerase during replication, resulting in gains/losses hamartomas of the mesodermal portion of the hair disk, of repeat units, causing cancer predisposition. The main usually occurring as multiple small papules. Acrochordons phenotypic manifestations related to this disease are lung are small outgrowths of epidermal and dermal tissue, which cysts, leading to , and a 7-fold increased risk may be pedunculated, smooth or irregular, flesh-colored and for renal neoplasia, although other neoplastic manifestations benign; they usually appear as pedunculated skin tags, have been described in BHD-affected individuals. Of occurring principally on the neck, eyelids, upper chest, and particular interest is the often reported genotype/ axillae in older women (3). correlation between FLCN mutations and risk of colon or The clinical extracutaneous characteristic manifestations breast cancer. This paper describes our current knowledge on include an increased risk for a spectrum of histological types the association between BHD and cancer predisposition and of renal carcinoma, and pulmonary cysts that usually lead to briefly summarizes our experience in this field. spontaneous pneumothorax. Of BHD syndrome patients and of BHD syndrome family members screened for lung cysts, The Birt Hogg Dubé syndrome (BHD) (OMIM 135150) is a 24% and 34%, respectively, had a history of spontaneous rare dominantly inherited autosomal genodermatosis, first pneumothorax (4), often occurring isolated and as the earliest described as an inherited skin disorder in 1977 and clinical symptom, so that clinicians assumed that characterized by a predisposition to the development of a spontaneous pneumothorax is a prominent feature of BHD triad of cutaneous signs including acrochordons and multiple syndrome (5-7), whose risk is increased by 50-fold compared hamartomas of the hair follicle such as fibrofolliculoma and with control populations (8). On the other hand, the relative trichodiscoma (1). risk of BHD-affected individuals for developing is about 9 times the odds of those who are not affected (8). Renal tumors are usually multiple and bilateral and appear with a spectrum of histological features of Correspondence to: Raffaele Palmirotta, MD, Ph.D., Department of chromophobe, oncocytoma, and hybrid tumors, more rarely Laboratory Medicine and Advanced Biotechnologies, IRCCS San of clear cell and papillary renal cancer (3). Raffaele, Via della Pisana 235, 00163, Rome, Italy. Tel: +39 There are numerous reports that describe a wide spectrum 0666130425, Fax: +39 0666130407, e-mail: raffaele.palmirotta@ of neoplastic phenotypic manifestations in BHD-affected sanraffaele.it individuals, including for example lipoma, melanoma, Key Words: Birt Hogg Dubé syndrome, folliculin, cancer parathyroid adenoma (3) or thyroid gland alterations, as predisposition, review. found in the original family described by Birt, Hogg and

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Dubé (1), but the significance of these associations has not through its interaction with FNIP1 and FNIP2, might been statistically substantiated. The association with colonic represent a downstream effector of the mammalian target of polyps and colonic adenocarcinoma still remains uncertain rapamycin (mTOR), or adenosine monophosphate-activated (8, 9). This paper describes our current knowledge on the protein kinase (AMPK) and a modulator of energy/nutrient- association between BHD and cancer predisposition and sensing signaling pathways by some as-yet-unknown briefly summarize, our own experience in this field (10), molecular mechanisms (21). with a particular emphasis on breast cancer predisposition in Using fluorescent in situ hybridization in healthy and BHD patients. neoplastic human tissues, it was demonstrated that FLCN mRNA was predominantly expressed in various tissues, The BHD Gene including the skin and its appendages, the distal nephron of the kidney, stromal cells and type 1 pneumocytes of the lung, The gene responsible for BHD was firstly identified in 2001, epithelial ducts of the breast, acinar cells of the pancreas, simultaneously in two different laboratories using serous gland of parotid and ovary. No expression was seen polymorphic microsatellite markers to perform a genome- in colon mucinous glands and epithelium (22). Another study wide linkage analysis on large BHD families and mapping in which FLCN mRNA levels in 20 different normal human the BHD gene to 17p12q11.2 (11, 12). tissues were compared showed the highest levels of transcript The gene sequence was identified in 2002 by positional to be in testis, ovary, brain and lung (21). cloning (13). The gene, named folliculin and approved with As for its distribution in neoplastic tissues, FLCN was found the symbol FLCN (OMIM# 607273, GenBank accession to be overexpressed in proliferating epithelial fibrofolliculomas, number AF517523 - NM_144997.5) contains 14 , 11 but significantly reduced in renal tumor tissues from BHD of which are codifying. patients regardless of histological type. Although the The FLCN transcript mRNA, starting from the first ATG significance of FLCN expression remains to be established, of exon 4, encodes a 579 protein, highly these data certainly suggest some function of the FLCN protein conserved between humans and homologs in mice, in many tissues, including the target organs skin, lung and Drosophila, and Caenorhabditis elegans. kidney, characterizing the BHD phenotype, and confirm the Numerous mutations have been described in the FLCN tumor suppressor function of FLCN in kidney cancer (22). gene, the most frequent being a hot spot occurring within a polycytosine C8 tract of exon 11 and resulting in Lung Cysts and Pneumothorax truncated folliculin; this has been found in the germ line of 44% of BHD patients (13). The mutation is probably due to As stated above, chief components of the BHD syndrome a slippage in DNA polymerase during DNA replication, phenotype are pulmonary cysts, leading to emphysema and leading to gains or losses of repeat units, as happens for spontaneous recurring pneumothorax. The presence of lung other causing cancer predisposition (5, 9). However, cysts in association with BHD syndrome was first confirmed mutations located elsewhere in the coding sequence are in 1999, in a study of three extended families affected by heterogeneous and several reports suggest that all translated renal tumors and characteristic skin manifestations (23). The exons might be mutated (14, 15). risk of BHD patients developing spontaneous pneumothorax, The first online database (http://www.skingenedatabase.com) a condition in which rupture of a cyst causes air to enter the detailing all FLCN variants reported in the literature was pleural space with resultant lung collapse, is increased 50- developed during the past year. To date, the FCLN database fold compared with control populations (5, 8). Histologically, describes 53 unique germline mutations, including a hot spot pulmonary cysts appear as cystic dilatation of alveolar spaces mutation (1285dup-delC), and 31 single that can reach the size of few millimeters in diameter (3). In polymorphisms (SNPs) (16). However, the fact that a significant several cases, the presence of lung cysts and subsequent proportion of FLCN mutations is described in should be taken spontaneous pneumothorax is the only phenotypic into account in the mutational screening of the gene, and should manifestation of the disease and is not associated with other lead to study of the overall coding region (17). events, such as classical involvement of skin and kidney tumors (7, 6, 14). FLCN Protein It is noteworthy that FLCN mRNA has been shown to be strongly expressed within the connective tissue of the The BHD gene encodes a 64-kDa protein called folliculin normal lung and lung blebs resected from a BHD patient (FLCN), whose functions are not completely understood. with spontaneous pneumothorax (22). It was also assumed Recent studies have identified two FLCN-interacting that the predominant subpleural location of the lung cysts is , FLCN-interacting protein 1 (FNIP1) (18) and caused by a distinctive role of FLCN in the periphery of the FLCN-interacting protein 2 (FNIP2) (19, 20). FLCN, lung (6).

752 Palmirotta et al: Birt Hogg Dubé Syndrome and Cancer Predisposition (Review)

The frequent occurrence of lung cysts and pneumothorax in have led to the hypothesis that, relying on clinical evidence, BHD patients and the evidence that pulmonary features may colon cancer is an associated phenotypic manifestation of precede the development of fibrofolliculomas and renal tumors BHD (9). However, an epidemiological study published in has been confirmed by several studies (5-8). For this reason, 2002 showed no association between BHD syndrome and many researchers today suggest that BHD syndrome be colon cancer or polyps (8). considered in the differential diagnosis of spontaneous Despite the statistical data, there is evidence of a close pneumothorax, even in the absence of characteristic skin link between colon cancer and FLCN gene alterations. lesions and renal tumors, possibly using molecular analysis (5). Indeed, a mutational study performed on sporadic colorectal cancer showed that the poly C8 tract of the Renal Tumors FLCN gene is an effective target of microsatellite instability (MSI), with a frequency comparable with that of other The renal associated with BHD are bilateral and target genes. These data give reason to believe that FLCN is multifocal rather than unilateral and solitary. Tumors occur a putative target gene involved in the development of in a variety of histological types, with different percentages, colorectal carcinomas with MSI (39). The involvement of according to various papers (9, 16, 24-26). The most frequent the FLCN gene in colorectal tumor progression is also BHD-associated renal tumors are chromophobe renal-cell confirmed by the presence of LOH at the chromosomal carcinomas (34%) and hybrid chromophobe oncocytomas region surrounding the FLCN locus in sporadic colorectal (50%) (24). Other renal tumors include clear-cell carcinomas tumors without MSI (40). (9%), oncocytomas (5%), and, rarely, papillary tumors (2%) No mRNA expression of FLCN was seen in epithelium (16, 24-26). Renal cancer associated with BHD syndrome and mucinous glands of colon and data regarding expression occurs at a mean age of 50.7 years (24), although other cases in colorectal tumoral tissues are not yet available (21, 22). have been reported with a much lower age of onset (9). These observations in colorectal cancer do not indicate a The search for a second somatic alteration of the FLCN tumor suppressor role for FLCN, such as for renal tumors, gene in the renal tumor tissue from BHD patients carrying but suggest a different pathway of carcinogenesis may germline FLCN mutations has confirmed the presence of a involve other mechanisms of genomic instability. second mutation or loss of heterozygosity (LOH) in 70% of Functional studies are still required in order for us to tumors (27). Inactivation of both copies of the FLCN gene understand the biological role of FLCN in colorectal occurred in all histological types of renal tumors, suggesting carcinogenesis. Nonetheless, recent topic reviews (41), and that the second FLCN inactivation rises at an early stage of extensive screening studies carried out on families with renal tumorigenesis and supporting the hypothesis that FLCN BHD continue to report the presence of colon cancer, or is a . Somatic FLCN gene mutations colonic polyposis associated with BHD (10, 42). Indeed, in were also found in cases of sporadic renal cancer, indicating recent work, Kluger et al. reported colorectal polyps that FLCN is intimately involved in kidney tumorigenesis (including a tubulovillous adenoma with high-grade (28, 29). These data were also confirmed in animal models in dysplasia and a benign gastric polyp) in 50% of BHD which the biallelic inactivation of the respective FLCN gene patients analyzed (43). homolog determines a phenotype corresponding to human BHD-associated renal cancer (30, 31). Consistent with these Breast Cancer results, FLCN mRNA expression was elevated in distal nephron and collecting duct of normal kidney; conversely The first evidence of a possible association between breast mRNA expression was hardly detectable in BHD-associated cancer and BHD syndrome was found in a large six- renal tumors, including clear cell, papillary, oncocytoma, generation Swedish family with BHD (Table I). A genome- chromophobe and oncocytic hybrid histotypes (22). wide linkage analysis using polymorphic microsatellite markers on this family led to the identification of the FLCN Colon Polyps and Tumors locus on chromosome 17p12q11.2. The authors described two cases of breast fibrobroadenomatosis in a mother and a Early reports, even before the syndrome was clinically daughter of the third and fourth generations, respectively, characterized, suggested that BHD was associated with a commenting that since fibroadenoma of the breast is very predisposition for the development of intestinal adenomatous common in the general population, its association with BHD polyps with histological features of marked dysplasia and could have been unrelated and needed to be further explored colon carcinoma (32, 33). Over the years, thanks to increased (11). Subsequently, the same authors reported that mutational knowledge of the clinical features of the disease, several analysis of the same family did not identify any germline groups have reported numerous cases of colorectal polyps sequence variant of FLCN. However, in this study, they and neoplasia in families with BHD (34-38), findings that identified a sporadic case with clinical evidence of

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Table I. Spectrum of germline FLCN mutations and phenotypic features of Birt Hogg Dubé syndrome patients with breast tumours reported in the literature.

Reference FLCN mutation Age at cancer Breast disease Other cancer Renal Lung cysts/ diagnosis tumor pneumo- (years) thorax

Khoo et al. 2001 (11) NA 58 Fibroadenomatosis of the breast - Cysts No NA 81 Fibroadenomatosis of the breast Sarcoma dorsi Cysts No Khoo et al. 2002 (9) NA 61 Sarcoma Colon polyps No Yes Gunji et al. 2007 (5) nt 1795 ins 38 Familiality* Vocal cord nodules, No Yes CCACCCT myoma of the uterus, carcinoma of thyroid Leter et al. 2008 (15) 1110dupG (Ala219fs) 44 Breast cancer - No No 1740dupC (His429fs) 60 Breast cancer Basal cell cancer No No of the skin; inverted papilloma of the nose. 1065_1066delGCinsTA 53 Benign breast disease - No Yes Toro et al. 2008 (45) ND ND Breast cancer ND ND ND Palmirotta et al. 2008 (10) 1345delAAAG 44 Breast cancer Colon cancer No No Ishiiet al. 2009 (44) IVS5 - exon 6 10bp del 29 Breast cancer - No Yes Kluger et al. 2009 (43) Exon 11 1285dup ND Familiality for melanoma, Colonic polyp, Cysts Yes (1733insC) breast and jaw cancer* hepatic angioma and (family)# polycystic ovaries nodules (family)# (family)# Exon 4 -3del (458delG) 49 Breast cysts and nodules Thyroid nodule Cysts Yes Exon 9 890_893del 50 Breast cysts Colonic adenomatous No Yes (1345_1348del) polyps with mild dysplasia

NA: Not available; *familiality for breast tumor; #clinical features observed in other family members; ND: not determined.

fibrofolliculomas, pneumothorax, colon polyps and breast of 50 families, Toro et al. described a series of neoplastic cancer but without any germline FLCN mutation (9), events, such as squamous cell carcinoma, Hodgkin’s disease, probably due to the presence of a sequence variant in a non- uterine cancer, prostate cancer and rhabdomyoma, rarely coding region. associated with classical BHD phenotype. In this context, an Breast cancer was also identified by Ishii et al. in a 29- isolated case of breast cancer without any clinical or year-old Japanese woman with radiological evidence of molecular findings was also reported (45). More recently, multiple cysts of different sizes in the lung, who belonged to Kluger et al. analyzed 22 BHD-affected patients from 10 a family with BHD with a deletion of 10 from unrelated French families, reporting a history of breast intron 5 to exon 6 of the FLCN gene (44). Similarly, family cancer in some members of a family, but no medical or history of breast carcinoma was reported in another Japanese molecular data of these individuals were analyzed (43). Two case of a 38-year-old female BHD patient, carrying an FLCN women with multiple breast nodules and cysts were also in exon 12, with recurrent pneumothorax described in two other families with no evidence of breast episodes, vocal cord nodules, myoma of the uterus and cancer (43). In these cases, authors accurately described the carcinoma of thyroid (5). Others reported the occurrence of presence of benign and malignant mammary tumors and breast cancer in BHD patients. Leter et al., in a study suggested, for the first time in literature, that benign breast performed on 20 families with BHD, observed a series of nodules and cysts examined needed specific clinical extracutaneous tumors including colorectal adenoma, oral surveillance (43). fibroma, lipoma, fibrosarcoma, skin basal cell carcinoma, Our experience on breast cancer in BHD patients is related skin squamous cell carcinoma, non-Hodgkin lymphoma, and to the mutational screening performed on two families from two cases of breast cancer, at the age of 44 (1110dupG ) and central Italy who were referred to our institutions following a of 60 (1740dupC) years, and a case of benign breast disease request for dermatological medical advice. In this study, we at the age of 53 years (15). Moreover, in an extensive study demonstrated the occurrence of two novel frameshift

754 Palmirotta et al: Birt Hogg Dubé Syndrome and Cancer Predisposition (Review)

Conclusion mutations located respectively in exons 5 (802insA) and 9 (1345delAAAG) of the FLCN gene, along with a homozygous sequence variant inintron 9 (IVS9 +5C>T). The potential From the data reported here, it is possible to deduce that relevance of exon 9 mutations in cancer predisposition for the small number of cases and the limited clinical BHD kindreds was also discussed, as the proband of the first information reported in the literature do not allow a clear family had a history of breast cancer at the age of 44 years interpretation of the results not a clear association of and of colon cancer at the age of 56 years. This patient was a cancer with BHD. One limitation of previous studies is carrier of the 1345delAAAG frameshift mutation, and the that certain forms of cancer, such as colorectal or breast latter was associated with a wide variety of tumors, including tumors, have been described to a lesser extent, putting stomach, colon and parotid cancer found in other family greater emphasis on the classic clinically overlapping members. Given the early onset of breast cancer and the lack disorders, such as cutaneous manifestations of the of a positive family history, we hypothesized that breast cancer syndrome, spontaneous pneumothorax and renal tumors. might be another rare component of the spectrum of tumors Regarding breast cancer, it should also be considered that, associated with BHD (10). Moreover, we should consider that given the high frequency of this malignancy in the general FLCN mRNA is highly expressed in the epithelial mammary female population, the cases described may simply be gland ductal cells of normal breast tissue, whereas a lower phenocopies. Nonetheless, additional studies are needed to expression is found at the level of fibroblasts and surrounding clarify this latter point because despite the small number stromal tissue. A strong expression of FLCN in tissues with a of cases described, breast cancer is also often reported as secretory function, such as pancreas, tonsil germinal center, part of the phenotypic spectrum of BHD at official and spleen white pulp, parotid gland and, in particular, breast institutional web sites (e.g.: http:// www.ncbi.nlm.nih.gov/sites/ tissue ductal cells, suggests a potential secretory role of this GeneTests and http:// www.bhdsyndrome.org/). The genes protein. Of interest, different breast tumors, including ductal, so far clearly associated with hereditary forms of breast lobular and mucinous carcinoma, as well as normal breast cancer are BRCA1 and BRCA2, while a small fraction of tissue, show a high expression of FLCN mRNA (22). These risk can currently be attributed to germline mutations in findings are markedly divergent from those observed in renal other genes, such as p53, ataxia-telangiectasia mutated gene cancer. Indeed, in the latter, the reduced expression of the (ATM), cadherin 1 (CDH1), phosphatase and tensin protein is consistent with the molecular data of a second homolog (PTEN), serine/threonine protein kinase 11 somatic gene mutation, suggesting a tumor suppressor role for (STK11) and mismatch repair genes (MMRs) (15). The data FLCN protein (27-29). While genotype–phenotype so far reported, often associated with an early age of onset correlations remain to be elucidated for BHD, given the high of breast cancer in patients with mutations in the FLCN frequency of breast cancer in the general female population, gene, suggest a possible association between germline additional studies are needed to clarify this point. FLCN mutation and the risk of breast cancer, although environmental or additional genetic factors may be involved, Other Lesions with Uncertain Association such as related genes co-segregating with FLCN or the possible presence of modifying genes in some of the BHD Several reports have described other additional cutaneous family members. Regarding polyps and colorectal tumors, phenotypic manifestations in BHD-affected individuals, the molecular data suggest a probable carcinogenetic including perivascular fibroma (46), angiofibroma (47), oral mechanism involving DNA mismatch repair defects, papules (48, 23) lipoma (23), collagenoma (23) and melanoma chromosomal rearrangements and other epigenetic events, (23, 49). Due to the sporadic occurrence of these lesions, a real including mutation in oncogenes and oncosuppressors association such as for fibrofolliculoma, trichodiscoma and related to FLCN gene. acrochordon, with BHD syndrome has not been definitively Given all these considerations, the opportunity for early proven (3). diagnosis makes it imperative to define phenotypic Furthermore, several other tumor types have occasionally features of disease, with the aim of improving been reported in association with BHD, such as the thyroid management for possible future cancer and associated gland alterations of the original family described by Birt, Hogg, disorder development in patients with BHD syndrome. and Dubé (1), ovarian cysts (42), cutaneous neurothekeoma and However, whilst awaiting future characterization of meningioma (50), multiple lipomas (38), parathyroid adenoma mutations associated with BHD and well-defined (38), angiolipoma and collagenoma (23), flecked genotype–phenotype correlations, it is important that all chorioretinopathy (51), chorioretinal lesions (51, 42) and parotid patients with BHD syndrome are screened not only for oncocytoma (14, 52, 4). However, their real association with classical related pathologies, such as for renal tumors and BHD syndrome has not yet been clinically validated and pneumothorax, but also for disorders that may be more additional studies specifically addressing this issue are required. than just chance associations.

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Acknowledgements 13 Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, We wish to thank Barbara Leone for her excellent technical assistance. Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg The Authors declare that there is no conflict of interest in regard to C, Lerman MI, Linehan WM, Zbar B and Schmidt LS: this paper. This study was partially supported by an Italian Ministry Mutations in a novel gene lead to kidney tumors, lung wall of Health Research Grant RFPS-2006-7-342220 and ACC-WP 3/1b. defects, and benign tumors of the hair follicle in patients with the Birt Hogg Dubé syndrome. Cancer Cell 2: 157-164, 2002. References 14 Schmidt LS, Nickerson ML,Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, 1 Birt AR, Hogg GR and Dubé WJ: Hereditary multiple Morrison P, Maher ER, Walther MM, Zbar B and Linehan WM: fibrofolliculomas with trichodiscomas and acrochordons. 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26 Pavlovich CP, Grubb RL 3rd, Hurley K, Glenn GM, Toro J, 39 Shin J-H, Shin Y-K, Ku J-L, Jeong S-Y, Hong S-H, Park S-Y, Schmidt LS, Torres-Cabala C, Merino MJ, Zbar B, Choyke P, Kim W-H and Park J-G: Mutations of the Birt Hogg Dubé Walther MM and Linehan WM: Evaluation and management of (BHD) gene in sporadic colorectal carcinomas and colorectal renal tumors in the Birt Hogg Dubé syndrome. J Urol 173: 1482- carcinoma cell lines with microsatellite instability. J Med Genet 1486, 2005. 40: 364-367, 2003. 27 Vocke C, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, 40 Kahnoski K, Khoo SK, Nassif NT, Chen J, Lobo GP, Segelov E Torres-Cabala CA, Merino MJ, Walther MM, Zbar B and and Teh BT: Alterations of the Birt Hogg Dubé gene (BHD) in Linehan WM: High frequency of somatic frameshift BHD gene sporadic colorectal tumours. J Med Genet 40(7): 511-515, 2003. mutations in Birt Hogg Dubé-associated renal tumors. 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Hautarzt 47: 304-306, 1996. 38 Chung JY, Ramos-Caro FA, Beers B, Ford MJ and Flowers F: Multiple lipomas, angiolipomas and parathyroid adenomas in a patient with Birt Hogg Dubé syndrome. Int J Dermatol 35: 365- Received October 27, 2009 367, 1996. Accepted January 12, 2010

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