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 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 76-78

Topical sirolimus in facial angiofibroma


1 Department of Dermatology, Government Medical College, Bhavnagar, Gujarat, India
2 Department of Pharmacology, Government Medical College, Bhavnagar, Gujarat, India

Date of Web Publication31-Dec-2018

Correspondence Address:
Dr. Hita Hemant Mehta
Department of Dermatology, Government Medical College, Bhavnagar, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_21_18

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  Abstract 

We represent a case of 11-year-male child with multiple facial angiofibromas who showed moderate improvement after application of 0.1 and 1% sirolimus. We evaluated the results clinically and dermoscopically.

Keywords: Facial angiofibroma, sirolimus, tuberous sclerosis complex


How to cite this article:
Gajjar PC, Mehta HH, Barvaliya M, Lakhotia R. Topical sirolimus in facial angiofibroma. Indian J Drugs Dermatol 2018;4:76-8

How to cite this URL:
Gajjar PC, Mehta HH, Barvaliya M, Lakhotia R. Topical sirolimus in facial angiofibroma. Indian J Drugs Dermatol [serial online] 2018 [cited 2019 Jul 18];4:76-8. Available from: http://www.ijdd.in/text.asp?2018/4/2/76/249184


  Introduction Top


Tuberous sclerosis complex (TSC) is a genodermatoses characterized by hamartomas in multiple organs such as the skin, brain, eyes, kidney, and heart. Among all, skin is the most commonly involved organ, the manifestations of which mainly comprise angiofibromas, shagreen patch, white ovoid or ash-leaf macules, and periungualfibomas.[1] Facial angiofibromas are pathognomonic cutaneous findings which occur in 70%–80% cases of TSC. They pose a great psychological and cosmetic distress as they are refractory to treatment. There are multiple therapeutic options described for treating angiofibromas.[2] Here, we are sharing a case of an 11-year-old child showing improvement in color, size, and number of facial angiofibromas after topical application of sirolimus.


  Case Report Top


An 11-year-old male child born to nonconsanguineous marriage presented to us with the complaint of multiple asymptomatic skin to brown-colored small, round, elevated skin lesions on the face for 2 years.

Except the facial lesions, child did not have any other cutaneous manifestations. He did not reveal any history of seizures, decreased vision, changes in weight, and bowel habits or early puberty. Similar complaint and history were not elicited from other family members.

On examination, we found multiple (30), discrete, small, round, firm, well-defined dome-shaped, reddish-brown telangiectatic papules present on cheeks, nose, and forehead. Few papules coalesced to form plaque.

Routine investigations such as complete blood count, renal and liver function tests, and viral markers were carried out before and after 3 months of starting topical sirolimus. Extracutaneous involvement was excluded by carrying out appropriate investigations such as computed tomography scan brain, Chest X-ray, and fundus examination. Histopathology of facial lesions confirmed the case as angiofibroma by the presence of concentric arrangement of collagen bundles around multiple hair follicles and dilated blood vessels.

Topical sirolimus was prepared in pharmacology department of the institute after crushing the 1 mg tablets of sirolimus and mixing it with white petrolatum jelly in sterilized airtight metal containers to prepare a concentration of 0.1 and 1%. Prior written informed consent was obtained from the guardian. The patient was advised twice daily application and explained regarding the side effects of topical sirolimus.

We evaluated the patient by digital photographs, dermoscopy, and FASI (facial angiofibroma severity index).[2] About 0.1% topical rapamycin was given for 1 month for a trial purpose which was increased to 1% topical sirolimus for the next 3 months.

Pre and postanalysis at monthly intervals are mentioned in [Table 1], [Figure 1] and [Figure 2]. We observed gradual decrease in the size of angiofibromas on the face as the duration of treatment increased. Color of the lesion also changed from reddish-brown to light-brown. Fortunately, patient did not experience any side effects such as redness, burning, or irritation.
Table 1: Facial angiofibroma severity index

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Figure 1: Clinical photographs

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Figure 2: Dermoscopic evaluation

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Patient presented to us late after 4th month of application so there was a little increase in the size of lesions.


  Discussion Top


TCS is an autosomal dominant neurocutaneous syndrome caused by mutation in two genes: TCS 1 and TCS 2. The disease was first recognized in the 19th century by Rayer and Bournville. The disease manifests by overstimulation of mammalian target of rapamycin (mTOR) complex 1 through dysfunction of two regulatory proteins-hamartin and tuberin. This results in uncontrolled cell growth and proliferation giving rise to hamartomas in multiple organs such as the skin, brain, eyes, kidney, and heart.[1],[2],[3],[4]

Cutaneous manifestations of TCS include facial angiofibromas (previously named “adenoma sebaceum”), forehead fibrous plaques, shagreen patch, hypomelanotic or confetti-like macules and periungual fibromas (Koenen's tumors).[1],[2],[3]

Facial angiofibromas are the most common cutaneous finding of TSC which are included as major diagnostic criteria in the “International tuberous sclerosis complex consensus conference 2012.”[3] They manifest as multiple, symmetrical reddish-brown dome-shaped papules on the face which is often cosmetically disfiguring for the child and parents. Invasive procedures such as cryotherapy, radiofrequency, dermabrasion, excision, peeling, and lasers are used to treat adenoma sebaceum, but all these procedures carry a risk of permanent scarring, the requirement of sedation, and incomplete removal. As the disease commonly manifests in the pediatric age group, there is always a need for a noninvasive method of getting rid of facial adenoma sebaceum.[5],[6]

Rapamycin (sirolimus) is a macrocyclic lactone isolated from soil bacterium “Streptomyces hygroscopicus.” It is an antimalignant drug which was previously used in transplant recipients and as a drug-eluting stent. However, recently, its antineoplastic and antiangiogenic action has been reported in benign tumors of TCS such as facial angiofibroma, renal angiomyolipoma, and subependymal astrocytoma. Angiofibromas of TCS shows overactivation of mTOR and overexpression of vascular endothelial growth factor both of which promote angiogenesis. Rapamycin inhibits mTOR activity, the transition from G1 to S phase, T lymphocyte formation, keratinocyte proliferation, and neutrophilic inflammatory activity.[2],[5],[7]

The role of rapamycin was discovered in TCS after Hofbauer et al. observed a decrease in the size of facial angiofibomas and renal angiomyolipoma following use of systemic sirolimus in a renal transplant patient. However studies have found that oral rapamycin carries risk for carcinoma, hypersensitivity, hypercholesterolemia, and hypertension.[5],[7] Growing tumors in early stage of life have more proliferative component thus sirolimus would be more effective in early childhood.[2],[3] This explains the reason for the drastic improvement in angiofibromas in our pediatric patient.

Wataya-Kaneda et al. have reported the effect of different topical concentrations of sirolimus in angiofibromas for varying duration.[8]

To watch for any adverse effects, we started with 0.1% topical rapamycin for the 1st month and later increased the concentration to 1% resulting in marked improvement which is similar to the observation in Indian study.[1]

We observed that after 1 month of applying 0.1% topical rapamycin, FASI score reduced from 6 to 5. At the end of 3 months, lesions decreased to the size of a pinhead and faded in color to light brown. FASI reduced to a score of 4 at the end of the 3rd month which later increased to 5 at the end of 4th month as the patient presented late for follow-up. This suggests that the effect of topical sirolimusis transient and needs long-term maintenance for effective results. Similar finding was mentioned by Cinar et al.[3] Dermoscopically, we observed decrease in size and fading of color of yellowish globules observed in lesions on the cheeks [Table 1] and [Figure 1], [Figure 2].

Few studies have reported dryness, mild burning, and erythema with topical application of sirolimus.[8] However, fortunately, our patient tolerated the medication very well without any side effects or adverse events.

Tu et al. monitored blood levels of sirolimus after topical application and found them to be below the immunosuppressive limit.[9] However due to the lack of advanced facilities in our institute, we could not measure the plasma level of the drug.

Thus, our case report will add to the very little evidence available on the effectiveness of topical sirolimus in facial angiofibromas. It is a safer and easier modality compared to other invasive methods. Limitation of topical sirolimus is that long-term treatment increases the cost of total treatment. Till now, studies were carried out only for a limited duration. Hence, more studies are needed on large scale of subjects for a longer duration for standardizing the concentration of sirolimus required to fade facial angiofibromas as well as nondermatological benign tumors of TCS.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This study was financially supported by the Department of Dermatology, Government Medical College, Bhavangar.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Schwartz RA. Facial angiofibromas of tuberous sclerosis treated with topical sirolimus in an Indian patient (commentary on article by Resham J. Vasani). Dermatol Ther 2016;29:70-1.  Back to cited text no. 1
    
2.
Salido-Vallejo R, Ruano J, Garnacho-Saucedo G, Godoy-Gijón E, Llorca D, Gómez-Fernández C, et al. Facial angiofibroma severity index (FASI): Reliability assessment of a new tool developed to measure severity and responsiveness to therapy in tuberous sclerosis-associated facial angiofibroma. Clin Exp Dermatol 2014;39:888-93.  Back to cited text no. 2
    
3.
Cinar SL, Kartal D, Bayram AK, Canpolat M, Borlu M, Ferahbas A, et al. Topical sirolimus for the treatment of angiofibromas in tuberous sclerosis. Indian J Dermatol Venereol Leprol 2017;83:27-32.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277:805-8.  Back to cited text no. 4
    
5.
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. 5
    
6.
Salido-Vallejo R, Garnacho-Saucedo G, Moreno-Giménez JC. Opciones terapéuticas actuals para los angiofibromasfaciales. Actas Dermosifiliogr 2014;105:558-68.  Back to cited text no. 6
    
7.
Herry I, Neukirch C, Debray MP, Mignon F, Crestani B. Dramatic effect of sirolimus on renal angiomyolipomas in a patient with tuberous sclerosis complex. Eur J Intern Med 2007;18:76-7.  Back to cited text no. 7
    
8.
Wataya-Kaneda M, Nakamura A, Tanaka M, Hayashi M, Matsumoto S, Yamamoto K, et al. Efficacy and safety of topical sirolimus therapy for facial angiofibromas in the tuberous sclerosis complex: A randomized clinical trial. JAMA Dermatol 2017;153:39-48.  Back to cited text no. 8
    
9.
Tu J, Foster RS, Bint LJ, Halbert AR. Topical rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: Follow up of a pilot study and promising future directions. Australas J Dermatol 2014;55:63-9.  Back to cited text no. 9
    


    Figures

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    Tables

  [Table 1]



 

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