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Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dube syndrome: a double-blind placebo-controlled randomized split-face trial.

ABSTRACT:

Background

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR). Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas) in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD.

Methods

We performed a double blinded, randomised, facial left-right controlled trial of topical rapamycin 0.1% versus placebo in 19 BHD patients. Trial duration was 6 months. The primary outcome was cosmetic improvement as measured by doctors and patients. Changes in fibrofolliculoma number and size were also measured, as was occurrence of side effects.

Results

No change in cosmetic status of fibrofolliculomas was reported in the majority of cases for the rapamycin treated (79% by doctors, 53% by patients) as well as the placebo treated facial sides (both 74%). No significant differences between rapamycin and placebo treated facial halves were observed (p?=?1.000 for doctors opinion, p?=?0.344 for patients opinion). No significant difference in fibrofolliculoma number or change in size of the fibrofolliculomas was seen after 6 months. Side effects occurred more often after rapamycin treatment (68% of patients) than after placebo (58% of patients; p?=?0.625). A burning sensation, erythema, itching and dryness were most frequently reported.

Conclusions

This study provides no evidence that treatment of fibrofolliculomas with topical rapamycin in BHD results in cosmetic improvement.

Trial registration

ClinicalTrials.gov NCT00928798.

SUBMITTER: Gijezen LM

PROVIDER: S-EPMC4049818 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome: a double-blind placebo-controlled randomized split-face trial.

Gijezen Lieke M C LM Vernooij Marigje M Martens Herm H Oduber Charlene E U CE Henquet Charles J M CJ Starink Theo M TM Prins Martin H MH Menko Fred H FH Nelemans Patty J PJ van Steensel Maurice A M MA

PloS one 20140609 6

<h4>Background</h4>Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previousl ...[more]

PMID: 24910976

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Project description:RationaleSpontaneous pneumothorax is a common complication of Birt-Hogg-Dubé syndrome (BHD).ObjectivesThe optimal approach to treatment and prevention of BHD-associated spontaneous pneumothorax, and to advising patients with BHD regarding risk of pneumothorax associated with air travel, is not well established.MethodsPatients with BHD were recruited from the Rare Lung Diseases Clinic Network and the BHD Foundation and surveyed about disease manifestations and air travel experiences.ResultsA total of 104 patients completed the survey. The average age at diagnosis was 47 years, with an average delay from first symptoms of 13 years. Pulmonary cysts were the most frequent phenotypic manifestation of BHD, present in 85% of patients. Spontaneous pneumothorax was the presenting manifestation that led to the diagnosis of BHD in 65% of patients, typically after the second episode (mean, 2.4 episodes). Seventy-nine (76%) of 104 patients had at least one spontaneous pneumothorax during their lifetime, and 82% had multiple pneumothoraces. Among patients with multiple pneumothoraces, 73% had an ipsilateral recurrence, and 48% had a subsequent contralateral spontaneous pneumothorax following a sentinel event. The mean ages at first and second pneumothoraces were 36.5 years (range, 14-63 yr) and 37 years (range, 20-55 yr), respectively. The average number of spontaneous pneumothoraces experienced by patients with a sentinel pneumothorax was 3.6. Pleurodesis was generally performed after the second (mean, 2.4) ipsilateral pneumothorax and reduced the ipsilateral recurrence rate by half. A total of 11 episodes of spontaneous pneumothorax occurred among eight patients either during or within the 24-hour period following air travel, consistent with an air travel-related pneumothorax rate of 8% per patient and 0.12% per flight. Prior pleurodesis reduced the occurrence of a subsequent flight-related pneumothorax.ConclusionsSpontaneous pneumothorax is an important, recurrent manifestation of pulmonary involvement in patients with BHD, and pleurodesis should be considered following the initial pneumothorax to reduce the risk of recurrent episodes. In general, in patients with BHD, pneumothorax occurs in about 1-2 per 1,000 flights, and the risk is lower among patients with a history of prior pleurodesis.

Project description:Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, expressing a novel protein called folliculin. We report the clinical and genetic studies of four sporadic BHD cases and four families with a total of 23 affected subjects. Haplotype analysis of these families using BHD linked markers showed they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified two germline mutations on exon 11 (c.1733insC and c.1733delC) in three of four families as well as two of four sporadic cases. A novel somatic mutation, c.1732delTCinsAC, was detected in a BHD related chromophobe renal carcinoma. Our results confirmed the (C)8 tract in exon 11 as a mutational hot spot in BHD and should always be considered for future genetic testing. Our observation also indicated that the second hit (of Knudson's two hit theory) in some BHD related tumours is in the form of somatic mutation rather than LOH. In a large French family in which eight affected subjects carry the c.1733delC mutation, a phenocopy who has multiple episodes of spontaneous pneumothorax was identified. A total of five mutation carriers (aged between 37 to 66) did not have any evidence of BHD features, suggesting either reduced penetrance or late age of onset of the disease. In addition, six out of eight affected subjects who have positive germline mutation have confirmed neoplastic colonic polyps, indicating that colorectal neoplasia is an associated feature of BHD in some families. Our studies have observed several interesting genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset of disease; (4) association with colorectal neoplasia in some families; and (5) somatic mutation instead of LOH as the second hit in BHD tumours.