Topical Rapamycin for Facial Angiofibromas in a Child with Tuberous Sclerosis Complex (TSC): A Case Report and Long-Term Follow-up

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease characterized by excess cell growth and proliferation, resulting in benign tumors and other abnormal tissue in multiple organs, including the skin [1, 2]. TSC is caused by inactivity of either of the two tumor suppressor genes, TSC1 or TSC2, encoding hamartin and tuberin [3, 4]. These proteins play an important role in the control of cell proliferation and differentiation through negative regulation of the mammalian target of rapamycin complex 1 (mTORC1). mTORC1 inhibitors such as rapamycin (sirolimus) or everolimus suppress tumor growth by reestablishing inhibition of mTORC1 and have been used as a targeted therapy for non-dermatologic manifestations in TSC (e.g., subependymal giant cell astrocytomas or kidney angiomyolipomas) [5].

Facial angiofibroma, previously known as ‘adenoma sebaceum’, is the most common TSC lesion to occur on the face [6] and represents a visible and often disfiguring stigma of the disease [7]. Invasive treatment options including cryosurgery, curettage, dermabrasion, chemical peeling, excision, and laser therapy are often used to treat disfiguring or bleeding lesions [8]. Benefits of these invasive procedures have to be balanced against the risks of permanent scarring, sedation in medically complex patients and incomplete removal of lesions as well as costs. Off-label use of topical rapamycin has been suggested as a non-invasive alterative approach to treating facial angiofibromas in pediatric TSC patients [9, 10].

We present a 12-year-old girl with a definitive diagnosis of TSC (TSC2 mutation) [11] and wide-spread disfiguring facial angiofibromas (Fig. 1a, b). Other TSC-related manifestations include subependymal nodules, focal epilepsy, intellectual disability, autism spectrum disorder, a cardiac rhabdomyoma, renal angiomyolipoma, retinal astrocytoma, scoliosis and primary enuresis. After obtaining consent, the patient received a twice-daily treatment every-day schedule with a 0.1% rapamycin ointment. The 100 g ointment was compounded by a local pharmacy, using 100 crushed 1-mg sirolimus oral tablets, paraffin and petrolatum.

This treatment regimen, started in August 2013, led to a marked reduction of angiofibromas during the first 16 weeks (Fig. 1c). No adverse effects were observed during the treatment period, and negative plasma rapamycin levels were reassuring against significant systemic drug levels. After a course of almost 1 year, when almost all angiofibromas had vanished (Fig. 2), the topical treatment was discontinued for 3 months and recurrence was evaluated. Previously faded angiofibromas were found to reoccur (Fig. 3a). Therefore, topical rapamycin therapy was restarted, again with a marked treatment response (Fig. 3b). We evaluated the increased size of previously faded angiofibromas after discontinuing treatment because of the patient’s adolescence and not for any ‘rebound effect.’ At the time of this report, the patient is still using the off-label medication with good response. Informed consent was obtained from the patient and her parents for being included in the study.

Emerging evidence suggests that topical mTORC1 inhibitors, such as rapamycin, appear to be safe and effective treatment options for TSC-related cutaneous manifestations, although long-term outcome data are pending [8]. To the best of our knowledge, this report of a 3-year follow-up is the longest published to date. Table 1 summarizes previously used topical rapamycin therapy for angiofibromas with at least 6-month treatment regimes. Topical rapamycin appears safe, but long-term maintenance therapy is necessary to prevent facial lesions from regrowth. There is only a single published randomized controlled trial evaluating topical rapamycin therapy versus placebo [12]. Although the subjects in the treatment arms reported greater subjective improvement compared to subjects in the placebo arm, the study was not powered to reach statistical difference. Therefore, further randomized controlled clinical trials and direct comparison to invasive surgical treatment modalities are clearly desirable to establish the optimal treatment protocols and dosage for topical mTORC1 inhibitors.