References for this Review were found through a search of Pubmed by use of the terms “Birt-Hogg-Dubé syndrome”, “fibrofolliculoma”, or “FLCN”. Reference lists of relevant articles were reviewed. Only full-text articles were included. No date or language restricitons were used. Selected references on associated topics were also included.
ReviewBirt-Hogg-Dubé syndrome: diagnosis and management
Introduction
In 1977, Birt, Hogg, and Dubé described a pedigree in which several family members had skin lesions, consisting of “fibrofolliculomas with trichodiscomas and acrochordons”.1 Birt-Hogg-Dubé syndrome (BHD) is currently defined as an autosomal dominant condition, caused by germline mutations in the FLCN (folliculin) gene, and characterised by skin fibrofolliculomas (figure 1), multiple lung cysts, spontaneous pneumothorax, and renal cancer (Online Mendelian Inheritance in Man #135150).
In 2001, a BHD-associated gene locus was localised to chromosome 17p11.2 by linkage analysis.2, 3 Subsequently, truncating germline mutations were identified in a novel gene, the FLCN (BHD) gene, coding for a protein of unknown function called folliculin (FLCN).4 At present, about 200 families with BHD with pathogenic FLCN mutations have been reported worldwide.5, 6, 7, 8, 9, 10, 11 Roth and colleagues12 first observed bilateral renal cancer in a 61-year-old patient with BHD, in 1993, and now an increased risk of renal cancer in carriers of FLCN mutations is firmly established.13, 14, 15, 16 Multiple lung cysts and spontaneous pneumothorax are also typical complications of the syndrome.14, 17
BHD is probably under-diagnosed because of the wide variability in its clinical expression. Patients might present with renal cancer18, 19, 20 or pneumothorax,6, 21, 22, 23, 24, 25 both of which most often occur sporadically. An estimated 25% of FLCN-mutation carriers older than 20 years of age do not manifest skin lesions,5, 7 whereas other mutation carriers have inconspicuous fibrofolliculomas.
FLCN is located on chromosome 17p11.2; the gene contains 14 exons and encodes folliculin, an evolutionary conserved protein of 579 aminoacids that has no major homology to any other human protein. The function of folliculin is largely unknown. Somatic second-hit mutations identified in BHD-associated renal tumours26 are consistent with a tumour-suppressor function for FLCN. In line with these findings, loss of FLCN mRNA expression was found in renal tumours from patients with BHD.27 However, FLCN mRNA was reported to be strongly expressed in fibrofolliculomas27 and Van Steensel and colleagues28 did not detect loss of heterozygosity in fibrofolliculomas, suggesting that mechanisms of tumorigenesis might differ in renal and skin tumours.
The Nihon rat model for BHD harbours a germline mutation of the rat Flcn orthologue.29 In this animal model, renal cancer develops with high penetrance and with histological features that resemble human chromophobe renal cancer.30 In heterozygous rats, introduction of wild-type Flcn resulted in suppression of renal carcinogenesis.31 Fibromatous tumours associated with surgical incisions were observed; however, this phenomenon has not been reported in humans.32
Lingaas and co-workers33 investigated an inherited cancer syndrome in German Shepherd dogs that showed multifocal renal cystadenocarcinoma and nodular dermatofibrosis. The researchers identified a missense mutation in the canine orthologue of the FLCN gene as the cause of this condition. Second-hit mutations were found in most of the renal tumours and in about a third of the early cystic renal lesions.34, 35 Loss of heterozygosity was not found in skin tumours, a result that is similar in humans.28
The energy-sensing mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of several hereditary hamartoma syndromes, including BHD.36, 37 Baba and colleagues38 identified a 130-kDa FLCN-interacting protein, FNIP1, and showed that it interacted with 5′AMP-activated protein kinase (AMPK), a protein involved in the mTOR pathway. An FNIP homologue, FNIP2, was found to interact with FLCN and AMPK.39, 40 Two studies described renal tumours and cysts and activation of mTOR in kidney-targeted BHD conditional knockout mice.41, 42 In this animal model, the mTOR-inhibitor rapamycin diminished kidney pathology and increased survival.
The tuberous-sclerosis-complex genes TSC1 and TSC2 encode proteins that regulate the mTOR pathway, and two studies43, 44 highlighted the overlapping clinical features of BHD and tuberous sclerosis complex (skin hamartomas, pulmonary cysts, pneumothorax, and renal tumours). However, yeast (Schizosaccharomyces pombe) that were missing the homologue of human FLCN had a phenotype opposite to yeast deficient for TSC1 or TSC2.43 Downregulation of FLCN leads to mTOR inhibition; by contrast, downregulation of TSC proteins leads to mTOR activation.44 The precise role of folliculin in the mTOR pathway requires further elucidation, and it seems likely that folliculin has several functions. Clarifying the role or roles of folliculin in the molecular pathogenesis of renal cancer might lead to targeted therapy in selected patients.
A germline FLCN mutation was found by sequence analysis, in 51 of 61 families (84%) with BHD.4, 5 Most of the reported pathogenic FLCN mutations are frameshift or nonsense mutations that lead to protein truncation, and a small percentage are splice-site alterations. A mononucleotide tract of eight cytosines within exon 11 has been identified as a hypermutable hotspot;4, 45 the most frequently observed mutation is a cytosine insertion c.1285dupC.5, 7 Very few missense FLCN mutations were reported (eg, 1523A→G [Lys508Arg]).7 Families without a detectable mutation might harbour a genomic deletion or amplification. Recently, an MLPA (Multiplex Ligation-dependent Probe Amplification) kit for FLCN deletion and amplification analysis has been developed. An FLCN mutation database has been established by Wei and colleagues46 and by the European BHD Consortium.47 So far, no gene other than FLCN has been implicated in BHD. In this Review, we summarise the diagnosis and management of BHD. Most of the recommendations are based on expert opinion and may serve as a basis for collaborative studies that could lead to evidence-based recommendations in the future.
Section snippets
The skin
Skin lesions in patients with BHD usually appear after the age of 20 years, as multiple, dome-shaped, whitish papules in the face. These lesions are mainly on the nose and cheeks (figure 1), can be common on the neck, and are sometimes on the trunk or the ears. Histologically, the skin tumours are benign hair follicle tumours designated as fibrofolliculoma (figure 2).
Birt and colleagues1 described fibrofolliculomas, trichodiscomas, and acrochordons as a triad of skin lesions that characterise
Criteria for diagnosis
DNA-based diagnosis of hereditary tumour syndromes has led to new classifications of these conditions based on the underlying gene defects. BHD was formerly defined by the presence of at least five to 10 fibrofolliculomas, of which at least one papule was diagnosed histologically.13, 45 However, the identification of FLCN defects in families with BHD has led to new insights in the penetrance and clinical variability of this syndrome. For example, FLCN-mutation carriers might not manifest any
Genetic testing
FLCN is currently the only gene known to be associated with BHD. DNA-based diagnosis should ideally consist of sequence analysis and a test for exonic deletions and amplifications. Genetic testing should always involve genetic counselling. Mutation detection is recommended even when the clinical diagnosis of BHD is unambiguous: detection of a pathogenic FLCN mutation not only confirms the diagnosis in the index patient but also allows presymptomatic testing of unaffected at-risk relatives. This
The skin
Treatment for skin fibrofolliculomas should be discussed, since the psychological burden of having numerous facial fibrofolliculomas should not be underestimated. However, current therapeutic options are limited. Case reports indicate that laser ablation using an erbium:YAG or fractional CO2 laser is not curative, but gives temporary improvement.79, 80, 81 Al-Daraji and colleagues82 reported successful shave and cautery treatment. Farrant and Emerson83 advocated curettage and hyfrecation of
Conclusion
BHD syndrome was first characterised on the basis of skin fibrofolliculomas—one of the major features. Multiple fibrofolliculomas, histologically verified, are probably diagnostic for the syndrome, although a distinct syndrome with fibrofolliculomas or trichodiscomas only has not been excluded. For the differential diagnosis, tuberous sclerosis complex is an important consideration, since fibrofolliculomas in BHD and angiofibromas in tuberous sclerosis complex have overlapping features. With
Search strategy and selection criteria
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