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

Lieke M C Gijezen, Marigje Vernooij, Herm Martens, Charlene E U Oduber, Charles J M Henquet, Theo M Starink, Martin H Prins, Fred H Menko, Patty J Nelemans, Maurice A M van Steensel, Lieke M C Gijezen, Marigje Vernooij, Herm Martens, Charlene E U Oduber, Charles J M Henquet, Theo M Starink, Martin H Prins, Fred H Menko, Patty J Nelemans, Maurice A M van Steensel

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Skin features in TSC and…
Figure 1. Skin features in TSC and BHD.
Photographs taken from a TSC and a BHD patient show angiofibromas and fibrofolliculomas, respectively. Notice the resemblance between the two types of lesion.
Figure 2. Trial outline.
Figure 2. Trial outline.
* The patient who was lost to follow-up at 3 months was excluded from the analysis of the 3 month results. ** For the patients who were lost to follow-up at 6 months, the 3-month data were carried forward in the analysis of the 6-month results.
Figure 3. Photographic recording of cosmetic status…
Figure 3. Photographic recording of cosmetic status during rapamycin treatment.
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.
Figure 4. Changes in cosmetic status of…
Figure 4. Changes in cosmetic status of fibrofolliculomas after treatment with rapamycin scored by doctors and patients.
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.
Figure 5. Changes in the number of…
Figure 5. Changes in the number of fibrofolliculomas after treatment with rapamycin.
BHD patients with facial fibrofolliculomas were treated with topical rapamycin and placebo for six months. The number of fibrofolliculomas in a predefined area of the face was determined and compared to baseline. The reduction in the number of fibrofolliculomas was stronger upon placebo treatment.
Figure 6. Local side effects of topical…
Figure 6. Local side effects of topical rapamycin treatment.
Side effects of both topical rapamycin and placebo treatment were registered at each clinical assessment. Burning, erythema, dryness and itching were the most commonly reported local side effects. All side effects other than dryness and itching were reported more frequently for the rapamycin treated facial half.

References

    1. Hornstein OP, Knickenberg M (1975) Perifollicular fibromatosis cutis with polyps of the colon—a cutaneo-intestinal syndrome sui generis. Arch Dermatol Res 253: 161–175.
    1. Birt AR, Hogg GR, Dubé WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113: 1674–1677.
    1. Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, et al. (2007) Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med 175: 1044–1053.
    1. Roth JS, Rabinowitz AD, Benson M, Grossman ME (1993) Bilateral renal cell carcinoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol 29: 1055–1056.
    1. Toro JR, Glenn G, Duray P, Darling T, Weirich G, et al. (1999) Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135: 1195–1202.
    1. Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, et al. (2002) Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26: 1542–1552.
    1. Al-Daraji WI, Al-Razag ZA, Craven N, Twaij Z (2005) Multiple hereditary facial papules. Clin Exp Dermatol 30: 309–310.
    1. Farrant PB, Emerson R (2007) Letter: hyfrecation and curettage as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome. Dermatol Surg 33: 1287–1288.
    1. Gambichler T, Wolter M, Altmeyer P, Hoffman K (2000) Treatment of Birt-Hogg-Dubé syndrome with erbium:YAG laser. J Am Acad Dermatol 43: 856–858.
    1. Jacob CI, Dover JS (2001) Birt-Hogg-Dubé syndrome: treatment of cutaneous manifestations with laser skin resurfacing. Arch Dermatol 137: 98–99.
    1. Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, et al. (2001) Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 69: 876–882.
    1. Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, et al. (2002) Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2: 157–164.
    1. Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, et al... (2013) The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1. Mol Cell. [Online] 2013 Oct 3. Available from: . [Accessed 13th November 2013]
    1. Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, et al. (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 103: 15552–15557.
    1. Baba M, Furihata M, Hong SB, Tessarollo L, Haines DC, et al. (2008) Kidney-targeted Birt-Hogg-Dubé gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst 100: 140–154.
    1. Chen J, Futami K, Petillo D, Peng J, Wang P, et al. (2008) Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia. PLoS One 3: e3581.
    1. Hasumi Y, Baba M, Ajima R, Hasumi H, Valera VA, et al. (2009) Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A 106: 18722–18727.
    1. Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, et al. (2012) Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol 36: 589–600.
    1. Inoki K, Corradetti MN, Guan KL (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37: 19–24.
    1. van Slegtenhorst M, Khabibullin D, Hartman TR, Nicolas E, Kruger WD, et al. (2007) The Birt-Hogg-Dubé and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe. J Biol Chem 282: 24583–24590.
    1. Toro JR (2008) Birt-Hogg-Dubé Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT et al.., editors. GeneReviews. Seattle (WA) [Online] 2008 Sept 9. Available from: . [Accessed 10th June 2013]
    1. Schaffer JV, Gohara MA, McNiff JM, Aasi SZ, Dvoretzky I (2005) Multiple facial angiofibromas: a cutaneous manifestation of Birt-Hogg-Dubé syndrome. J Am Acad Dermatol 53: S108–111.
    1. Hofbauer GF, Marcollo-Pini A, Corsenca A, Kistler AD, French LE, et al. (2008) The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br J Dermatol 159: 473–475.
    1. Haemel AK, O'Brian AL, Teng JM (2010) Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 146: 715–718.
    1. Wataya-Kaneda M, Tanaka M, Nakamura A, Matsumoto S, Katayama I (2011) A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity. Br J Dermatol 165: 912–916.
    1. Mutizwa MM, Berk DR, Anadkat MJ (2011) Treatment of facial angiofibromas with topical application of oral rapamycin solution (1mgmL(-1)) in two patients with tuberous sclerosis. Br J Dermatol 165: 922–923.
    1. Kaufman McNamara E, Curtis AR, Fleischer Jr AB (2012) Successful treatment of angiofibromata of tuberous sclerosis complex with rapamycin. J Dermatolog Treat 23: 46–48.
    1. Foster RS, Bint LJ, Halbert AR (2012) Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: a pilot study of four patients. Australas J Dermatol 53: 52–56.
    1. Truchuelo T, Diaz-Ley B, Rios L, Alcantara J, Jaen P (2012) Facial angiofibromas treated with topical rapamycin: an excellent choice with fast response. Dermatol Online J 18: 15.
    1. DeKlotz CM, Ogram AE, Singh S, Dronavalli S, MacGregor JL (2011) Dramatic improvement of facial angiofibromas in tuberous sclerosis with topical rapamycin: optimizing a treatment protocol. Arch Dermatol 147: 1116–1117.
    1. Leyden JJ, Shalita A, Thiboutot D, Washenik K, Webster G (2005) Topical retinoids in inflammatory acne: a retrospective, investigator-blinded, vehicle-controlled, photographic assessment. Clin Ther 27: 216–224.
    1. Ozolins M, Eady EA, Avery A, Cunliffe WJ, O'Neill C, et al. (2005) Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne. Health Technol Assess 9: iii–212.
    1. Liu W, Chen Z, Ma Y, Wu X, Jin Y, et al. (2013) Genetic Characterization of the Birt-Hogg-Dubé Syndrome Gene. PLoS One 8: e65869.
    1. Hudon V, Sabourin S, Dydensborg AB, Kottis V, Ghazi A, et al. (2010) Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin. J Med Genet 47: 182–189.
    1. Hartman TR, Nicolas E, Klein-Szanto A, Al-Saleem T, Cash TP, et al. (2009) The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis. Oncogene 28: 1594–1604.
    1. Claessens T, Weppler SA, van Geel M, Creytens D, Vreeburg M, et al. (2010) Neuroendocrine carcinoma in a patient with Birt-Hogg-Dubé syndrome. Nat Rev Urol 7: 583–587.
    1. Betschinger J, Nichols J, Dietmann S, Corrin PD, Paddison PJ, et al. (2013) Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell 153: 335–347.
    1. van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutierrez P, et al. (2007) Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. J Invest Dermatol 127: 588–593.
    1. Vernooij M, Claessens T, Luijten M, van Steensel MA, Coull BJ (2013) Birt-Hogg-Dubé syndrome and the skin. Fam Cancer 12: 381–385.
    1. Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, et al... (2013) Birt-Hogg-Dubé syndrome is a novel ciliopathy. Hum Mol Genet. [Online] 2013 Juli 6. Available from doi: 10.1093/hmg/ddt288 [Accessed 31st July 2013]
    1. Barrett CW, Hadgraft JW, Caron GA, Sarkany I (1965) The effect of particle size and vehicle on the percutaneous absorption of fluocinolone acetonide. Br J Dermatol 77: 576–578.
    1. Poulsen BJ, Young E, Coquilla V, Katz M (1968) Effect of topical vehicle composition on the in vitro release of fluocinolone acetonide and its acetate ester. J Pharm Sci 57: 928–933.
    1. Arellano A, Santoyo S, Martin C, Ygartua P (1999) Influence of propylene glycol and isopropyl myristate on the in vitro percutaneous penetration of diclofenac sodium from carbopol gels. Eur J Pharm Sci 7: 129–135.
    1. Nicolazzo JA, Morgan TM, Reed BL, Finnin BC (2005) Synergistic enhancement of testosterone transdermal delivery. J Control Release 103: 577–585.

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