Review Birt-Hogg-Dubé syndrome: diagnosis and management Fred H Menko, Maurice A M van Steensel, Sophie Giraud, Lennart Friis-Hansen, Stéphane Richard, Silvana Ungari, Magnus Nordenskjöld, Thomas v O Hansen, John Solly, Eamonn R Maher, on behalf of the European BHD Consortium Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition characterised clinically by skin fi brofolliculomas, Lancet Oncol 2009; pulmonary cysts, spontaneous pneumothorax, and renal cancer. The condition is caused by germline mutations in 10: 1199–206 the FLCN gene, which encodes folliculin; the function of this protein is largely unknown, although FLCN has been Department of Clinical linked to the mTOR pathway. The availability of DNA-based diagnosis has allowed insight into the great variation in Genetics, VU University Medical Centre, Amsterdam, expression of FLCN, both within and between families. Patients can present with skin signs and also with the Netherlands pneumothorax or renal cancer. Preventive measures are aimed mainly at early diagnosis and treatment of renal (F H Menko MD); Department cancer. This Review gives an overview of current diagnosis and management of BHD. of Dermatology and GROW Research School for Oncology and Developmental Biology, Introduction The Nihon rat model for BHD harbours a germline Maastricht University Medical In 1977, Birt, Hogg, and Dubé described a pedigree in mutation of the rat Flcn orthologue.29 In this animal Center, the Netherlands which several family members had skin lesions, consisting model, renal cancer develops with high penetrance and (M A M van Steensel MD); of “fi brofolliculomas with trichodiscomas and acro- with histological features that resemble human Laboratoire de Génétique & Réseau National INCa, Hôpital 1 30 chordons”. Birt-Hogg-Dubé syndrome (BHD) is currently chromophobe renal cancer. In heterozygous rats, Edouard Herriot, Lyon, France defi ned as an autosomal dominant condition, caused by introduction of wild-type Flcn resulted in suppression of (S Giraud MD); Department of germline mutations in the FLCN (folliculin) gene, and renal carcinogenesis.31 Fibromatous tumours associated Clinical Biochemistry, characterised by skin fi brofolliculomas (fi gure 1), multiple with surgical incisions were observed; however, this Rigshospitalet, University of Copenhagen, Denmark 32 lung cysts, spontaneous pneumothorax, and renal cancer phenomenon has not been reported in humans. (L Friis-Hansen MD, (Online Mendelian Inheritance in Man #135150). Lingaas and co-workers33 investigated an inherited T v O Hansen MSc); Génétique In 2001, a BHD-associated gene locus was localised to cancer syndrome in German Shepherd dogs that showed Oncologique EPHE-CNRS FRE 2,3 2939, Faculté de Médecine chromosome 17p11.2 by linkage analysis. Subsequently, multifocal renal cystadenocarcinoma and nodular Paris Sud, Réseau National INCa truncating germline mutations were identifi ed in a novel dermato fi brosis. The researchers identifi ed a missense and Centre Pilote Tumeurs gene, the FLCN (BHD) gene, coding for a protein of mutation in the canine orthologue of the FLCN gene as Rares INCa/AP-HP, Service unknown function called folliculin (FLCN).4 At present, the cause of this condition. Second-hit mutations were d’Urologie, Hôpital de Kremlin-Bicêtre, France about 200 families with BHD with pathogenic FLCN found in most of the renal tumours and in about a third (Prof S Richard MD); SS Biologia 5–11 34,35 mutations have been reported worldwide. Roth and of the early cystic renal lesions. Loss of heterozygosity Molecolare e Genetica, colleagues12 fi rst observed bilateral renal cancer in a was not found in skin tumours, a result that is similar in Departemento di Laboratorio, 28 Ospidale S Croce e Carle, Cuneo, 61-year-old patient with BHD, in 1993, and now an humans. Italy (S Ungari MD); Karolinska increased risk of renal cancer in carriers of FLCN The energy-sensing mammalian target of rapamycin University Hospital, 13–16 mutations is fi rmly established. Multiple lung cysts (mTOR) pathway has been implicated in the pathogenesis Stockholm, Sweden and spontaneous pneumothorax are also typical of several hereditary hamartoma syndromes, including (Prof M Nordenskjöld MD); 14,17 36,37 38 Myrovlytis Trust, London, UK complications of the syndrome. BHD. Baba and colleagues identifi ed a 130-kDa (J Solly PhD); Cancer Research BHD is probably under-diagnosed because of the wide FLCN-interacting protein, FNIP1, and showed that it UK Renal Molecular Oncology variability in its clinical expression. Patients might interacted with 5’AMP-activated protein kinase (AMPK), Group and Department of present with renal cancer18–20 or pneumothorax,6,21–25 both a protein involved in the mTOR pathway. An FNIP Medical and Molecular of which most often occur sporadically. An estimated homologue, FNIP2, was found to interact with FLCN and Genetics, University of Birmingham, and West 39,40 25% of FLCN-mutation carriers older than 20 years of AMPK. Two studies described renal tumours and cysts Midlands Regional Genetics age do not manifest skin lesions,5,7 whereas other Service, Birmingham Women’s mutation carriers have inconspicuous fi brofolliculomas. Hospital, UK FLCN is located on chromosome 17p11.2; the gene (Prof E R Maher MD) contains 14 exons and encodes folliculin, an evolutionary Correspondence to: Dr Fred H Menko, Department of conserved protein of 579 aminoacids that has no major Clinical Genetics, VU University homology to any other human protein. The function of Medical Centre, Amsterdam, folliculin is largely unknown. Somatic second-hit Netherlands mutations identifi ed in BHD-associated renal tumours26 fh [email protected] are consistent with a tumour-suppressor function for For more on the Online Mendelian Inheritance in Man FLCN. In line with these fi ndings, loss of FLCN mRNA genetic database see http:// expression was found in renal tumours from patients www.ncbi.nlm.nih.gov/omim with BHD.27 However, FLCN mRNA was reported to be strongly expressed in fi brofolliculomas27 and Van Steensel and colleagues28 did not detect loss of heterozygosity in fi brofolliculomas, suggesting that mechanisms of Figure 1: Multiple, dome-shaped, whitish papules on the nose and cheeks in tumorigenesis might diff er in renal and skin tumours. a 31-year-old carrier of an FLCN mutation www.thelancet.com/oncology Vol 10 December 2009 1199 Review and activation of mTOR in kidney-targeted BHD BHD. In this Review, we summarise the diagnosis and conditional knockout mice.41,42 In this animal model, the management of BHD. Most of the recommendations are mTOR-inhibitor rapamycin diminished kidney pathology based on expert opinion and may serve as a basis for and increased survival. collaborative studies that could lead to evidence-based The tuberous-sclerosis-complex genes TSC1 and TSC2 recommendations in the future. encode proteins that regulate the mTOR pathway, and two studies43,44 highlighted the overlapping clinical Clinical manifestations features of BHD and tuberous sclerosis complex (skin The skin hamartomas, pulmonary cysts, pneumothorax, and renal Skin lesions in patients with BHD usually appear after tumours). However, yeast (Schizosaccharomyces pombe) the age of 20 years, as multiple, dome-shaped, whitish that were missing the homologue of human FLCN had a papules in the face. These lesions are mainly on the nose phenotype opposite to yeast defi cient for TSC1 or TSC2.43 and cheeks (fi gure 1), can be common on the neck, and Downregulation of FLCN leads to mTOR inhibition; by are sometimes on the trunk or the ears. Histologically, contrast, downregulation of TSC proteins leads to mTOR the skin tumours are benign hair follicle tumours activation.44 The precise role of folliculin in the mTOR designated as fi brofolliculoma (fi gure 2). pathway requires further elucidation, and it seems likely Birt and colleagues1 described fi brofolliculomas, that folliculin has several functions. Clarifying the role or trichodiscomas, and acrochordons as a triad of skin roles of folliculin in the molecular pathogenesis of renal lesions that characterise BHD. Currently, fi brofolliculo- cancer might lead to targeted therapy in selected mas and trichodiscomas are considered to be part of a patients. morphological spectrum. Acrochordons, or skin tags, are A germline FLCN mutation was found by sequence common in the general population. In BHD, skin tags analysis, in 51 of 61 families (84%) with BHD.4,5 Most of might represent a phenotypic variant of fi bro- the reported pathogenic FLCN mutations are frameshift folliculoma.48–50 BHD-associated skin lesions might also or nonsense mutations that lead to protein truncation, include angiofi broma.51 Multiple facial angiofi bromas are and a small percentage are splice-site alterations. more typically associated with tuberous sclerosis than A mononucleotide tract of eight cytosines within exon 11 with BHD, which should be con sidered in the diff erential has been identifi ed as a hypermutable hotspot;4,45 the diagnosis of BHD. Oral lesions may also occur in BHD. most frequently observed mutation is a cytosine insertion Toro and co-workers13 found multiple, discrete soft c.1285dupC.5,7 Very few missense FLCN mutations were papules involving the lips, buccal mucosa, and gingiva in reported (eg, 1523A→G [Lys508Arg]).7 Families without a nine patients with BHD, under scoring the case report by detectable mutation might harbour a genomic deletion Nadershahi and colleagues.52 For more on the Multiplex or amplifi cation. Recently, an MLPA (Multiplex Ligation- The diagnosis of BHD-associated skin lesions is based Ligation-dependent Probe dependent Probe Amplifi cation) kit for FLCN deletion on both clinical presentation and histological examination. Amplifi cation kit see and amplifi cation analysis has been developed. An FLCN Multiple biopsies and sectioning of the lesions on several www.mlpa.com mutation database has been established by Wei and levels might be required for correct classifi cation. Expert For more on the 46 47 FLCN mutation databases colleagues and by the European BHD Consortium. So advice might be necessary when the diagnosis is in doubt.