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Year : 2015  |  Volume : 60  |  Issue : 2  |  Page : 165-169
Facial angiofibromas of tuberous sclerosis treated with topical sirolimus in an Indian patient

Department of Dermatology, K J Somaiya Hospital and Research Centre, Sion, Mumbai, Maharashtra, India

Date of Web Publication3-Mar-2015

Correspondence Address:
Resham J Vasani
A/1 Sharad Kunj, Dr. Moose Road, Thane - 400 602, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5154.152516

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Facial angiofibromas are the most visible and unsightly of all the cutaneous manifestations of tuberous sclerosis (TSC). A 17-year-old female, a known case of TSC, presented for the treatment of cosmetically disfiguring facial angiofibromas. She was started on twice daily application of 0.1% sirolimus ointment prepared from crushed tablets of sirolimus compounded in white soft paraffin. After 3 months of use, there was visible decrease in the erythema and the size of the angiofibromas. In an attempt to accelerate the response, the concentration was further increased to 1% sirolimus which was used for a month, resulting in a decrease not only in the size and redness but also in the number of the angiofibromas. The patient did not experience any cutaneous or systemic complications related to therapy. Sirolimus belongs to a novel class of anticancer drugs known as mTOR (mammalian target of Rapamycin) inhibitors. Sirolimus has been used as a targeted therapy for the renal and neurological manifestations of TSC. Topical preparation of sirolimus is not commercially available till date and hence preparations from crushed tablets or oral solution of sirolimus have been used with beneficial effects in treatment of angiofibromas especially in younger patients with flatter lesions. Randomized controlled trials are necessary to enable us to confirm the efficacy, long-term safety, the optimal dosage and possibility of reappearance once the drug is withdrawn. This is possibly the first case report of the use of topical sirolimus in India.

Keywords: Angiofibromas, rapamycin, sirolimus, tuberous sclerosis

How to cite this article:
Vasani RJ. Facial angiofibromas of tuberous sclerosis treated with topical sirolimus in an Indian patient. Indian J Dermatol 2015;60:165-9

How to cite this URL:
Vasani RJ. Facial angiofibromas of tuberous sclerosis treated with topical sirolimus in an Indian patient. Indian J Dermatol [serial online] 2015 [cited 2022 Sep 29];60:165-9. Available from:

What was known?
Sirolimus is a novel drug belonging to the class of mTOR inhibitors and has been successfully tried topically in the management of angiofibromas associated with tuberous sclerosis.

   Introduction Top

One of the most obvious cutaneous manifestations of tuberous sclerosis (TSC) is facial angiofibromas, which start appearing at 3 to 4 years of age. The number and size of angiofibromas varies markedly between patients, but they have the potential to become extremely unsightly. Typically, facial angiofibromas do not improve spontaneously and are frequently treated for the disfigurement.

Current treatments for facial angiofibromas include vascular lasers, ablative lasers and physically destructive techniques such as shave excision and electrodessication. Despite this proactive and costly approach, the outcomes are often less than satisfactory.

Oral sirolimus has already been used for the renal and neurological manifestations of TSC. In recent years it has been administered topically in varying concentrations for treatment of angiofibromas associated with TSC with good results. This is possibly the first report of the use of topical sirolimus in an Indian patient. The article further discusses the problems encountered with the use of the drug in the Indian scenario.

   Case Report Top

A 17-year-old female, a known case of TSC, presented to the outpatient department for the cosmetic treatment of disfiguring facial angiofibromas since 5 years of age. Dermatological examination revealed several other cutaneous manifestations characteristic of the disease apart from angiofibromas, namely ash leaf macules, shagreen plaque on the back and confetti like hypopigmented macules on the trunk. The patient also had history of convulsions and mental retardation. She had no known internal hamartomatous lesions.

She had undergone multiple sessions of electrodesiccation earlier with recurrence of lesions. In order to avoid an invasive procedure and its inherent complications, it was planned to start the patient on topical sirolimus.

Currently sirolimus is available in the international market in two formulations: Rapamune® oral solution (60 mg per 60 ml in an amber colored bottle) and Rapamune® tablet available in 1 mg and 2 mg strengths. Topical formulation of sirolimus is unavailable till date. Oral solution available commercially has been used topically as it is, or as a compounded product. Since there is no oral solution of sirolimus available in India, crushed tablets of sirolimus (Rapacan-1®, Biocon, India) were compounded in white soft paraffin using basic pharmacy equipment.

Prior to starting treatment, the complete blood count, hepatic and renal parameters of the patient were done and they were found to be normal. Since there are no available reports of tolerability of sirolimus in the Indian setting, it was thought prudent to start sirolimus in a low concentration of 0.1% and further increase the concentration according to the tolerability of the patient. Also, starting at a lower concentration would lower the cost of the medication for the patient, ensuring better patient compliance.

The patient was instructed to apply the ointment twice daily after washing and drying the face completely. After using the 0.1% preparation for 3 months, there was a definite decrease in the erythema as well as the size of the angiofibromas [Figure 1] and [Figure 2]. Encouraged by the results; in an attempt to accelerate the response, the concentration of sirolimus was increased to 1% which was used for a period of a month with a definite decrease in the size as well as number of angiofibromas with substantial decrease in the erythema [Figure 1] and [Figure 2].
Figure 1: (a) Pretreatment image, (b) after 3 months of topical 0.1% sirolimus ointment twice daily, (c) after 1 month of topical 1% sirolimus ointment twice daily

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Figure 2: (a) Pretreatment image, (b) after 3 months of topical 0.1% sirolimus ointment twice daily, (c) after 1 month of topical 1% sirolimus ointment twice daily

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The patient did not experience any cutaneous adverse effects throughout the treatment with topical sirolimus. As this report is being written, the patient is currently on treatment with 1% sirolimus ointment.

The complete blood count, renal and hepatic profile of the patient was monitored every 2 months and was found to be normal. It was not possible to measure the systemic absorption of the sirolimus on account of cost constraints.

   Discussion Top

TSC is an autosomal dominant genodermatosis characterized by development of hamartomatous tumors in multiple organs including brain, skin, kidney, heart and lungs. Facial angiofibromas are the most visible and unsightly of all the cutaneous manifestations of TSC and they are seen in up to 80% of the cases. They often result in a negative psychological impact on pediatric patients and stigmatization of their families.

Current treatment modalities include vascular lasers, ablative lasers and other destructive techniques such as shave excision, cryosurgery, dermabrasion, photodynamic therapy and electrodesiccation. Despite proactive and costly approaches, there is no sustained efficacy in the long term and the risks of complications like scarring continue to exist. Sedation utilized for these procedures poses a risk because of the underlying seizure disorders in these patients, so does anti epileptic loading and prolonged intubation.

Sirolimus is a lipophilic macrocyclic lactone which was first isolated from a soil bacterium Streptomyces hygroscopicus in Rapa Nui (Easter Island) in 1965, hence the old name Rapamycin. Sirolimus belongs to a novel class of anticancer drugs known as mTOR (mammalian target of Rapamycin) inhibitors. [1]

Sirolimus and the related mTOR inhibitor everolimus have been used as a targeted therapy for the renal and neurological manifestations of TSC. [2],[3],[4],[5],[6] A patient of TSC who was receiving oral sirolimus after undergoing renal transplantation had pronounced regression of her cutaneous angiofibromas and this triggered its use as a topical agent, in an attempt to minimize systemic toxicity.

In patients with TSC, the mTOR is aberrantly activated in fibroblast like cells located within the dermal layer of the skin. These cells produce an epidermal growth factor, epiregulin, which stimulates epidermal cell proliferation. [7] Hence, epidermal cells are produced at a faster rate than the ability to slough the dead cells from the skin surface. This overproduction of skin cells in conjunction with angiogenesis results in initial appearance and continued progression of facial angiofibromas over time. Angiofibromas of TSC shows prominent vascular component owing to increased expression of angiogenic factors like vascular endothelial growth factor (VEGF) and mTOR overactivation that promotes angiogenesis. Sirolimus binds with high specificity to mTOR and this binding results in inhibition of mTOR activity and ultimately downregulation of cell growth. [8] It also inhibits progression from G1 phase to S phase, suppresses T lymphocyte and antibody production, and inhibits keratinocytic proliferation and neutrophilic inflammatory activity [9],[10] Also, inhibition of the mTOR pathway decreases output of VEGF by inhibiting hypoxia-inducible factor expression and by directly repressing VEGF-stimulated endothelial cell proliferation. [11]

Sirolimus has a molecular weight of 914.2 grams/mol, allowing for it to be absorbed through the superficial layers of the epidermis to the deep dermal layer implicated in the development of facial angiofibromas. [12] Growing tumors which are probably due to greater proliferative component during early stages of life, could be more sensitive to the inhibitory action of sirolimus on mTOR and hence it is justifiable to initiate treatment as soon as the angiofibromas start to appear in early childhood.

Various investigators have used different concentrations of topical sirolimus for varying duration for the management of facial angiofibromas [Table 1].
Table 1: Use of topical sirolimus in the treatment of facial angiofibromas of tuberous sclerosis

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Hence, topical sirolimus is an effective treatment for angiofibromas especially in young children with flatter lesions, with the preparation formulated in petrolatum being well tolerated with no adverse effects. It is also cost effective if compared to hospital admission for laser therapy under general anesthesia with due risks.

The treatment considerations that would probably be more relevant in the Indian sitting are:

  • High cost of the medication-When the concentration of the medication was increased to 1%, the expenditure of the patient can be more than Rs 200 per day which is very high for economically strained conditions existing in India
  • It is practical to use commercially available oral solution of Sirolimus, since compounding pharmacies are not always readily accessible and the stability and efficacy of the compounded preparation cannot be ensured. Since oral solution was not available a topical preparation using crushed tablets of sirolimus was used in this case
  • Cutaneous irritation or burning sensation has been mentioned in the literature as the most common side effect after topical sirolimus. It has been advised to co-prescribe topical hydrocortisone 1% or desonide 0.05% lotion to counteract irritation and ensure compliance. [20] In this case, the patient tolerated the preparation very well
  • Though topically applied Sirolimus has minimal systemic absorption, it should have been monitored using chromatographic and immunoassay methodologies, which was not possible in a resource-constrained setting
  • The duration of treatment and the chances of recurrence are not defined. This makes the counseling of the patient difficult.

Thus, randomized controlled trials are necessary to enable us to confirm the efficacy of this treatment, its long term safety, the optimal dosage and possibility of reappearance once the drug is withdrawn. Also, given the small number of cases described to date, the most suitable presentation of the product has not yet been determined.

   References Top

Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci 2012;13:1886-918.  Back to cited text no. 1
Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358:140-51.  Back to cited text no. 2
Tarasewicz A, Debska-Slizien A, Konopa J, Zdrojewski Z, Rutkowski B. Rapamycin as a therapy of choice after renal transplantation in a patient with tuberous sclerosis complex. Transplant Proc 2009;41:3677-82.  Back to cited text no. 3
Birca A, Mercier C, Major P. Rapamycin as an alternative to surgical treatment of subependymal giant cell astrocytomas in a patient with tuberous sclerosis complex. J Neurosurg Pediatr 2010;6:381-4.  Back to cited text no. 4
Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363:1801-11.  Back to cited text no. 5
Micozkadioglu H, Koc Z, Ozelsancak R, Yildiz I. Rapamycin therapy for renal, brain, and skin lesions in a tuberous sclerosis patient. Ren Fail 2010;32:1233-6.  Back to cited text no. 6
Li S, Takeuchi F, Wang JA, Fan Q, Komurasaki T, Billings EM, et al. Mesenchymal-epithelial interactions involving epiregulin in tuberous sclerosis complex hamaratomas. Proc Natl Acad Sci U S A 2008;105:3539-44.  Back to cited text no. 7
Paghdal KV, Schwartz RA. Sirolimus (rapamycin): From the soil of Easter Island to a bright future. J Am Acad Dermatol 2007;57:1046-50.  Back to cited text no. 8
Hofbauer GF, Marcollo-Pini A, Corsenca A, Kistler AD, French LE, Wüthrich RP, et al. The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br J Dermatol 2008;159:473-5.  Back to cited text no. 9
Haemel, AK, O'Brian AL, Teng JM. Topical rapamycin: A novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 2010;146:715-8.  Back to cited text no. 10
Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 2006;66:5549-54.  Back to cited text no. 11
Koenig M, Hebert A, Roberson J, Samuels J, Slopis J, Woerner A, Northrup H. Topical Rapamycin therapy to alleviate the cutaneous manifestation of tuberous sclerosis complex - A double blind, randomised, controlled trial to evaluate safety and efficacy of topically applied Rapamycin. Drugs RD 2012:12:123-6.  Back to cited text no. 12
Wataya-Kaneda M, Tanaka M, Nakamura A, Matsumoto S, Katayama I. 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 2011;165:912-6.  Back to cited text no. 13
Mutizwa MM, Berk DR, Anadkat MJ. Treatment of facial angiofibromas with topical application of oral rapamycin solution (1 mgmL(-1)) in two patients with tuberous sclerosis. Br J Dermatol 2011;165:922-3.  Back to cited text no. 14
Truchuelo T, Díaz-Ley B, Ríos L, Alcántara J, Jaén P. Facial angiofibromas treated with topical rapamycin: An excellent choice with fast response. Dermatol Online J 2012;18:15.  Back to cited text no. 15
Foster RS, Bint LJ, Halbert AR. Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: A pilot study of four patients. Australas J Dermatol 2012;53:52-6.  Back to cited text no. 16
Salido R, Garnacho-Saucedo G, Cuevas-Asencio I, Ruano J, Galán-Gutierrez M, Vélez A, et al. Sustained clinical effectiveness and favourable safety profile of topical sirolimus for tuberous sclerosis - associated facial angiofibromas. J Eur Acad Dermatol Venereol. 2012;26:1315-8.  Back to cited text no. 17
Kaufman McNamara E, Curtis AR, Fleischer AB Jr. Successful treatment of angiofibromata of tuberous sclerosis complex with rapamycin. J Dermatolog Treat 2012;23:46-8.  Back to cited text no. 18
Valeron-Almazan P, et al. Topical Rapamycin solution to treat multiple facial angofibromas in a patient with tuberous sclerosis. Actas Dermosifiliogr 2012;103:165-6.  Back to cited text no. 19
Madke B. Topical rapamycin (sirolimus) for facial angiofibromas. Indian Dermatol Online J 2013;4:54-7.  Back to cited text no. 20
[PUBMED]  Medknow Journal  

What is new?
This is possibly the first case report of use of topical sirolimus in an Indian patient.


  [Figure 1], [Figure 2]

  [Table 1]

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