Topical Rapamycin as a Treatment for Fibrofolliculomas in Birt-Hogg-Dubé Syndrome: A Double-Blind Placebo-Controlled Randomized Split-Face Trial

Gijezen, Lieke; Vernooij, Marigje; Martens, Helmut; Oduber, Charlène E.U.; Henquet, C. J. M.; Starink, Th. M.; Prins, Martin H.; Menko, Fred H.; Nelemans, Patty J.; Steensel, M.A.M. van

doi:10.1371/journal.pone.0099071

Cited by 46 publications

(31 citation statements)

References 41 publications

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“…The skins lesions can be removed surgically – or with laser therapy or curettage for cosmetic reasons, but they tend to recur [190-193]. A recent trial of topical sirolimus has shown no improvement with regard to the number and size of fibrofolliculomas in patients with BHD [194]. …”

Section: Birt-hogg-dubé Syndromementioning

confidence: 99%

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

Daccord¹,

Nicod²,

Lazor³

2017

Respiration

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Cystic lung diseases constitute a distinct group of rare lung disorders, among which two result from monogenic defects affecting tumor suppressor genes: lymphangioleiomyomatosis, either sporadic or associated with tuberous sclerosis complex, and Birt-Hogg-Dubé syndrome. These disorders have similarities in their clinical expression, including occurrence in young adults, multiple pulmonary cysts, recurrent pneumothorax, skin hamartomas, and renal tumors. However, they markedly differ in their gender distribution, pathogenesis, disease course, and prognosis. Our knowledge on these two rare conditions is rapidly expanding. Management of lymphangioleiomyomatosis has substantially improved in the past decade with the understanding of its pathogenic mechanisms, the discovery of an effective therapy, and development of large cohorts and international guidelines. Birt-Hogg-Dubé syndrome has been described more recently and still awaits deeper understanding of its pathophysiology.

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Section: Birt-hogg-dubé Syndromementioning

confidence: 99%

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

Daccord¹,

Nicod²,

Lazor³

2017

Respiration

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“…Some therapeutic options are curettage/shave plus cautery, oral isotretinoin, carbon dioxide and erbium:YAG LASER and topical rapamycin. 1,3,11,12 Conclusions Birt-Hogg-Dubé syndrome is probably under-diagnosed because of the wide variability in its clinical expression. When examining patients with multiple facial papules the dermatologist should consider BHDS.…”

Section: 7mentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][10][11][12] BHDS predisposes to benign hair follicle hamartomas known as fibrofolliculomas (FF) and trichodiscomas (TD), acrochorda; lung disease (bibasilar cysts and, less frequently, pneumothorax); and kidney neoplasms with different histologic presentations. [1][2][3][4][5][6][7][8][10][11][12] The incidence of this syndrome is unknown but it is probably underdiagnosed given its variable penetrance and consequent range of clinical manifestations. 1 We describe two patients with BHDS carrying new FLCN mutations, not previously described in literature, and one of them with a type of adrenal gland tumor associated for the first time to this syndrome.…”

Section: Introductionmentioning

confidence: 99%

Birt-Hogg-Dubé Syndrome – report of two cases with two new mutations

Rato

Monteiro

Parente

et al. 2017

J Dermatol Case Rep

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Introduction: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genodermatosis characterized by cutaneous fibrofolliculomas and/or trichodiscomas, lung cysts, spontaneous pneumothorax and renal tumors. However, its clinical expression is highly variable. This syndrome is caused by germline mutations in the folliculin gene (FLCN) on chromosome 17p11.2.Main observations: Two men, 60 and 39-year-old, presented with a several year history of asymptomatic whitish papules scattered over the face and neck. Skin biopsies revealed fibrofolliculomas. The clinical diagnosis of BHDS was corroborated by identification of new heterozygotic mutations in FLCN gene, in exon 6 (C.573_574delinsT) and in exon 9 (c.1015C>T), respectively. Computed tomography scan of the thorax and abdomen showed pulmonary cysts with no suspicious kidneys lesions, and, in the case of the second patient, a mass in left adrenal gland. Laparoscopic left adrenalectomy was performed and histopathological examination was compatible with a malignant perivascular epithelioid cell tumor. Conclusions:The presence of multiple fibrofolliculomas should raise the suspicion of BHDS. Patients with this syndrome, regardless of the detected mutation, should be carefully monitored to ensure that potentially serious disease-related conditions can be detected early. (J Dermatol Case Rep. 2017; 11(1): 12-15)

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“…A double-blind randomized controlled trial of topical rapamycin (0.1% vs placebo) was performed in 19 BHD patients over a 6 month period (96). No clear change in the appearance, size or number of fibrofolliculomas was seen between rapamycin and placebo treatment.…”

Section: Potential Targeted Therapies For Bhd Syndromementioning

confidence: 99%

“…Partial rescue of the enlarged polycystic kidney phenotype in this in vivo model by mTOR inhibitor rapamycin was encouraging and suggested that targeting the mTOR pathway might be an effective therapeutic approach for treatment of BHD-associated renal tumors and cutaneous fibrofolliculomas. However, topical application of rapamycin in a Netherlands clinical trial failed to have any effect on treatment of fibrofolliculomas (96). Additionally, subsequent studies using several different heterozygous Flcn -knockout mouse models (52, 67) and a bhd mutant yeast strain (68), reported inhibition of mTOR signaling under Flcn deficiency.…”

Section: Expert Opinionmentioning

confidence: 99%

Clinical features, genetics and potential therapeutic approaches for Birt–Hogg–Dubé syndrome

Schmidt

Linehan²

2014

Expert Opinion on Orphan Drugs

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Introduction Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder that predisposes to fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal neoplasia. BHD is characterized by germline mutations in tumor suppressor FLCN. Inactivation of the remaining FLCN allele in kidney cells drives tumorigenesis. Novel FLCN-interacting proteins, FNIP1 and FNIP2, were identified. Studies with FLCN-deficient in vitro and in vivo models support a role for FLCN in modulating AKT-mTOR signaling. Emerging evidence suggests that FLCN may interact in a number of pathways/processes. Identification of FLCN’s major functional roles will provide the basis for developing targeted therapies for BHD patients. Areas covered This review covers BHD diagnostic criteria, clinical manifestations and genetics, as well as molecular consequences of FLCN inactivation. Recommended surveillance practices, patient management, and potential therapeutic options are discussed. Expert opinion In the decade since FLCN was identified as causative for BHD, we have gained a greater understanding of the clinical spectrum and genetics of this cancer syndrome. Recent studies have identified interactions between FLCN and a variety of signaling pathways and cellular processes, notably AKT-mTOR. Currently, surgical intervention is the only available therapy for BHD-associated renal tumors. Effective therapies will need to target primary pathways/processes deregulated in FLCN-deficient renal tumors and fibrofolliculomas.

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Topical Rapamycin as a Treatment for Fibrofolliculomas in Birt-Hogg-Dubé Syndrome: A Double-Blind Placebo-Controlled Randomized Split-Face Trial

Cited by 46 publications

References 41 publications

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

Birt-Hogg-Dubé Syndrome – report of two cases with two new mutations

Clinical features, genetics and potential therapeutic approaches for Birt–Hogg–Dubé syndrome

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