Ungual tumors, a major diagnostic criterion for tuberous sclerosis complex (TSC), are often symptomatic and have posed a therapeutic challenge.1 We present a case of successful treatment of a subungual fibroma with topical rapamycin.
A female toddler with known TSC presented with multiple skin lesions characteristic of TSC; these included 5 facial collagenomas, more than 20 hypopigmented macules and patches consistent with ash leaf macules, and bilateral subungual tumors of the first toenails with associated nail plate dystrophy (Figure, A). Facial angiofibromas were not present. Other manifestations of TSC included known cardiac rhabdomyoma diagnosed prenatally and multiple daily seizures since infancy. Genetic testing had revealed mutations in both TSC1 and TSC2.
A, At presentation, subungual tumors involving the patient's right great toe were causing distortion of the nail. B, At the 6-month follow-up after treatment with topical rapamycin, the subungual tumors were no longer noticeable, and dystrophy of the nail plate had subsided.
The patient was having pain associated with the subungual fibromas and nail plate distortion. Surgical intervention had previously been offered for treating the facial collagenomas and the subungual fibromas, but the parents had declined. After presentation to our clinic, topical rapamycin in a 1-mg/mL solution was prescribed to be applied twice daily to the collagenomas and under occlusion to the periungual and subungual areas of the first toenails. While there was minimal to no improvement in the facial collagenomas, improvement in the subungual tumors was observed at the 2-month follow-up. At the 6-month follow-up, the subungual tumors were no longer noticeable, and dystrophy of the nail plate had subsided (Figure, B). Treatment was then discontinued. There were no signs of recurrence of the fibromas 6 months later, at most recent follow-up. The topical rapamycin was well tolerated without complications.
Cutaneous stigmata of TSC can be very difficult to treat successfully, and, historically, primarily surgical interventions were considered to be the only options. Recently, several reports and small studies have demonstrated the safety and efficacy of topical rapamycin for facial angiofibromas in patients with TSC.2,3 A recent left vs right side of the face comparative study also demonstrated efficacy and good tolerability of topical rapamycin for the treatment of facial angiofibromas.4 Successful treatment of nonangiofibroma cutaneous manifestations of TSC has been sparse. To our knowledge, topical rapamycin has not been used successfully to treat the ungual fibromas of TSC. In our case, the use of topical rapamycin was well tolerated and resulted in the resolution of subungual tumors and rapid normalization of the overlying nail distortion.
The pathogenesis of TSC is characterized by an autosomal dominant mutation in TSC1 or TSC2 resulting in aberrant functioning of hamartin or tuberin, respectively. Tuberin, a GTPase-activating protein for Rheb, functions in a complex formed with hamartin. Rheb, which in turn activates mTOR, is inhibited in the presence of a normal tuberin-hamartin complex.5 In TSC, the hamartin-tuberin complex is unable to form, resulting in the constitutive activation of the mitogenic mTOR pathway. Rapamycin suppresses this pathway through the direct inhibition of mTOR.
While not entirely understood, an unrestrained mTOR pathway leads to upregulation of vascular endothelial growth factor (VEGF). It is suggested that rapamycin may exert its therapeutic effect on TSC lesions by directly killing tumor cells in addition to inhibiting VEGF production.6 Therefore, the same mechanism by which rapamycin reduces facial angiofibromas may also apply to nonangiofibroma cutaneous manifestations such as ungual tumors.
Patients with periungual and subungual fibromas associated with TSC are often quite symptomatic and often have significant distortion of the nail plate. Their treatment options have been quite limited to date. While further study is necessary, the experience with our patient suggests that topical rapamycin is a safe, well-tolerated, and potentially efficacious treatment for patients with ungual tumors associated with TSC.
Corresponding Author: Megha M. Tollefson, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (firstname.lastname@example.org).
Published Online: June 11, 2014. doi:10.1001/jamadermatol.2014.87.
Conflict of Interest Disclosures: None reported.
Muzic JG, Kindle SA, Tollefson MM. Successful Treatment of Subungual Fibromas of Tuberous Sclerosis With Topical Rapamycin. JAMA Dermatol. 2014;150(9):1024-1025. doi:10.1001/jamadermatol.2014.87