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

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</p

Birt-Hogg-Dubé syndrome: clinical and genetic studies of 20 families

Birt-Hogg-Dubé syndrome (BHD) is an autosomal-dominant genodermatosis characterized by skin fibrofolliculomas and an increased risk of spontaneous pneumothorax, renal and possibly other tumors. A causative gene (FLCN) on chromosome 17p has recently been identified. We here report clinical and genetic studies of 20 BHD families ascertained by the presence of multiple fibrofolliculomas or trichodiscomas in the proband. Pathogenic FLCN germline mutations were found in 11 (69%) of 16 probands tested and in 14 family members. Six different FLCN germline mutations were detected, four of which have not been reported previously. The clinical features were variable. None and less than 10 skin lesions were observed in two mutation carriers at the age of 67 and 29 years, respectively. Spontaneous pneumothorax was reported in four and renal carcinoma of mixed histological types in two of 36 BHD-affected individuals and/or FLCN mutation carriers. Both the prevalence of spontaneous pneumothorax and renal tumors appeared to be relatively low compared with previously reported data. Various other extracutaneous tumors were observed in 11 of 36 BHD-affected individuals and/or FLCN mutation carriers. This study of the second largest cohort to date contributes to the expanding data on the variable phenotype and underlying gene defects in BH

Renal imaging in 199 Dutch patients with Birt-Hogg-Dube syndrome: Screening compliance and outcome

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Condom use promotes regression of human papillomavirus-associated penile lesions in male sexual partners of women with cervical intraepithelial neoplasia

Penile HPV-associated lesions are frequently seen in male sexual partners of women with CIN. The natural course and clinical significance of these lesions are unclear. Women with CIN and their male sexual partners were randomized for condom use (condom group n = 68, noncondom group n = 68). Males were screened for the presence of penile lesions, i.e., flat lesions, papular lesions and condylomata acuminata, and of HPV in their penile swabs by PCR testing. Median follow-up time was 13.1 months (range 2.9-57.4). The outcome of our study was clinical regression of penile lesions defined as disappearance of lesions at penoscopy. Potentially prognostic factors, i.e., HPV status, lesion type and age, were studied as well. Outcomes were assessed in 57 men of the condom group and in 43 men of the noncondom group. Condom use shortened the median time to regression of flat penile lesions (7.4 months condom group vs. 13.9 months noncondom group; HR = 2.1, 95% CI 1.2-3.7). This effect was not found for papular lesions (HR = 0.5, 95% CI 0.1-2.8). HPV-negative men showed a significantly shorter median time to regression of flat lesions (3.8 months) compared to men with either HPV-positive status (8.5 months; HR = 0.4, 95% CI 0.2-0.9) or inconsistent HPV status (13.1 months; HR = 0.2, 95% CI 0.1-0.6). Regression of flat penile lesions is HPV-dependent and accelerated by condom use. This effect is probably the result of blocking viral transmission between sexual partners

Penile lesions and human papillomavirus in male sexual partners of women with cervical intraepithelial neoplasia

BACKGROUND: Genital human papillomavirus infection (HPV) is causally associated with cervical carcinomas and premalignant lesions. Limited information is available about the prevalence of HPV and penile lesions in male sexual partners of women with cervical intraepithelial neoplasia (CIN). OBJECTIVE: The aim of this study was to identify the presence of penile lesions and HPV in penile scrapings from male sexual partners of women with CIN. METHODS: One hundred seventy-five male sexual partners of women with CIN were screened by peniscopy after acetowhite staining and HPV testing on penile scrapings. RESULTS: Penile lesions were seen in 68% of the male sexual partners. More than one lesion type was diagnosed in 15%. Flat lesions, papular lesions, and condylomata acuminata were seen in 83%, 29%, and 4%, respectively. HPV was detected in 59% of the penile scrapings, containing mainly oncogenic HPV types. When penile lesions were present at peniscopy, 67% of penile scrapings were positive for HPV, whereas 37% were HPV-positive when no lesions were visible. CONCLUSIONS: Penile lesions are frequently found in sexual partners of women with CIN. Most of these lesions are subclinical (ie, only visible after acetowhite staining) and are often associated with the presence of high-risk HPV, indicating that male sexual partners of women with CIN might constitute a reservoir for high-risk HPV

Photographic recording of cosmetic status during rapamycin treatment.

<p>Close up of standardised facial photographs taken at baseline, 3 months and 6 months after starting treatment with topical rapamycin or placebo per facial half. Photos of a representative patient are shown, revealing no visible improvement or worsening of the facial fibrofolliculomas.</p

Changes in cosmetic status of fibrofolliculomas after treatment with rapamycin scored by doctors and patients.

<p>BHD patients with facial fibrofolliculomas were treated with topical rapamycin and placebo for six months. The degree of improvement compared to baseline was scored on a 7-point Likert scale by both doctors (A) and patients (B). Doctors and patients reported no change in the majority of cases. Patients reported improvement more frequently for the rapamycin compared to the placebo treated facial side.</p